Substituted benzyl amine compounds

ABSTRACT

Certain substituted benzyl amine compounds are histamine H 3  receptor and/or serotonin transporter modulators useful in the treatment of histamine H 3  receptor- and/or serotonin-mediated diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/806,169, filed Jun. 29, 2006, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to certain benzyl amine compounds,pharmaceutical compositions containing them, and methods of using themfor the treatment of disease states, disorders, and conditions mediatedby the histamine H₃ receptor and/or the serotonin transporter.

BACKGROUND OF THE INVENTION

The histamine H₃ receptor is primarily expressed in the mammaliancentral nervous system (CNS), with some minimal expression in peripheraltissues such as vascular smooth muscle. Several indications forhistamine H₃ antagonists and inverse agonists have been proposed basedon animal pharmacology and other experiments with known histamine H₃antagonists (e.g. thioperamide). (See: “The Histamine H₃ Receptor-ATarget for New Drugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier,1998; Morisset, S. et al., Nature 2000, 408, 860-864.) These includeconditions such as cognitive disorders, sleep disorders, psychiatricdisorders, and other disorders.

Compounds that possess histamine H₃ receptor activity and serotonintransporter (SERT) activity may be useful in the treatment ofSERT-mediated disorders such as substance abuse disorders and sexualdysfunction (including premature ejaculation), and particularlybeneficial in the treatment of depression. Activation of the H₃ receptoron neurons by histamine or an agonist decreases the release of severalneurotransmitters including noradrenaline and serotonin, keyneurotransmitters involved in depression (Hill, S. J. et al. Pharmacol.Rev. 1997, 49(3), 253-278). Although H₃ receptor antagonists alone maynot be capable of increasing serotonin levels in vivo to those requiredfor antidepressant effects, concomitant blockade of the SERT willsimultaneously decrease the neuronal reuptake of these neurotransmittermolecules, leading to enhanced concentrations of serotonin in thesynaptic cleft and an enhanced therapeutic effect and a potentiallyreduced side effect profile as compared to a compound with SERT activityalone.

Histamine H₃ antagonists have been shown to have pharmacologicalactivity relevant to several key symptoms of depression, including sleepdisorders (e.g. sleep disturbances, fatigue, and lethargy) and cognitivedifficulties (e.g. memory and concentration impairment), as describedabove. Therefore, a combined H₃/SERT modulating compound would providesymptomatic relief for the sleep disorders, fatigue, and cognitiveproblems during the first weeks of treatment, before the mood-elevatingeffect of the SERT modulation is noticed.

Compounds that have H₃ receptor activity and SERT activity have beendisclosed in U.S. Pat. Publ. US 2006/0194837 A1 (published Aug. 31,2006; based on U.S. patent application Ser. No. 11/300,880), U.S. Pat.Publ. US 2006/0293316 A1 (published Dec. 28, 2006; based on U.S. patentapplication Ser. No. 11/424,734), and U.S. Pat. Publ. US 2006/0287292 A1(published Dec. 21, 2006; based on U.S. patent application Ser. No.11/424,751), each of which is hereby incorporated by reference.

Aminomethyl phenyl ethers have been described by Pfizer, in Intl. PatentAppl. Publ. No. WO 01/72687, WO 02/18333, and U.S. Patent Appl. Publ.No. US 2002/0143003. Heteratom-linked aryl benzamides have beendescribed by Glaxo SmithKline, in Intl. Patent Appl. Publ. No. WO05/040144.

However, there remains a need for potent histamine H₃ receptor and/orserotonin transporter modulators with desirable pharmaceuticalproperties.

SUMMARY OF THE INVENTION

Certain benzyl amine derivatives have now been found to have histamineH₃ receptor and/or serotonin transporter modulating activity. Thus, theinvention is directed to the general and preferred embodiments defined,respectively, by the independent and dependent claims appended hereto,which are incorporated by reference herein.

In one general aspect the invention relates to a compound of thefollowing Formula (I):

wherein

-   one of R^(1a) and R^(1b) is

and the other is —H;

-   R² and R³ are each independently selected from the group consisting    of: —H; a —C₁₋₆alkyl group unsubstituted or substituted with —OH,    —OC₁₋₄alkyl, —NH₂, —N(R^(a))R^(b), or —F; —CO₂C₁₋₄alkyl; and a    monocyclic cycloalkyl group unsubstituted or substituted with    —C₁₋₄alkyl, —OH, halo, or —CF₃;    -   where R^(a) and R^(b) are each independently —H, —C₁₋₆alkyl, or        monocyclic cycloalkyl, or R^(a) and R^(b) taken together with        their nitrogen of attachment form a monocyclic heterocycloalkyl        group;    -   provided that R² and R³ are not both H;        or, alternatively,-   R² and R³ taken together with the nitrogen to which they are    attached form a saturated monocyclic heterocycloalkyl group    unsubstituted or substituted on a carbon ring member with one, two,    or three R^(d) moieties and substituted on a nitrogen ring member    with an R^(e) moiety;    -   where each R^(d) moiety is independently selected from the group        consisting of: —C₁₋₆alkyl; —C₁₋₄alkyl-OH; halo; —OH;        —OC₁₋₆alkyl; ipso-substituted —OC₂₋₃alkylO—; —CN; —NO₂;        —N(R^(g))R^(h); —C(O)N(R^(g))R^(h); —N(R^(g))SO₂C₁₋₆alkyl;        —C(O)C₁₋₆alkyl; —S(O)₀₋₂—C₁₋₆alkyl; —SO₂N(R^(g))R^(h); —SCF₃;        —CF₃; —OCF₃; —CO₂H; and —CO₂C₁₋₆alkyl;        -   where R^(g) and R^(h) are each independently —H or            —C₁₋₆alkyl, or R^(g) and R^(h) taken together with their            nitrogen of attachment form a monocyclic heterocycloalkyl            group; and    -   where R^(e) is selected from the group consisting of: —H; a        —C₁₋₆alkyl or —C(O)C₁₋₆alkyl group unsubstituted or substituted        with halo, —CN, —OH, —OC₁₋₄alkyl, or —CF₃; —C(O)CF₃;        —S(O)₀₋₂—C₁₋₆alkyl; —CO₂C₁₋₆alkyl; and a phenyl, monocyclic        carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic        carbon-linked heterocycloalkyl group, each unsubstituted or        substituted with —C₁₋₄alkyl, halo, —CN, —OH, —OC₁₋₄alkyl, or        —CF₃;-   q is 0 or 1;-   each R⁴ is independently —H or methyl, or both R⁴ substituents taken    together form a carbonyl;-   Y is —O—, —OCH₂—, —S—, —SO—, or —SO₂—;-   R⁵ is —H or —C₁₋₆alkyl;-   R⁶ is —H; or —C₁₋₆alkyl, —C₃₋₆alkenyl, —C₃₋₆alkynyl, monocyclic    cycloalkyl, or —C₁₋₆alkyl-(monocyclic cycloalkyl), each    unsubstituted or substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl,    halo, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, —CO₂H, or    —CO₂C₁₋₄alkyl;-   R⁷ is —H; or —C₁₋₆alkyl, —C₃₋₆alkenyl, —C₃₋₆alkynyl, monocyclic    cycloalkyl, or —C₁₋₆alkyl-(monocyclic cycloalkyl), each    unsubstituted or substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl,    halo, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, —CO₂H, or    —CO₂C₁₋₄alkyl;-   or R⁶ and R⁷ taken together with their nitrogen of attachment form a    saturated monocyclic heterocycloalkyl group unsubstituted or    substituted with —C₁₋₄alkyl, —OC₁₋₄alkyl, or halo; and-   Cyc is a phenyl or monocyclic carbon-linked heteroaryl group,    unsubstituted or substituted with one, two, or three R^(k) moieties;    -   where each R^(k) moiety is independently selected from the group        consisting of: —C₁₋₆alkyl, —CHF₂, —CF₃, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —OH, —OC₁₋₆alkyl, —OCHF₂, —OCF₃, —OC₃₋₆alkenyl,        —OC₃₋₆alkynyl, —CN, —NO₂, —N(R^(l))R^(m), —N(R^(l))C(O)R^(m),        —N(R^(l))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl,        —C(O)N(R^(l))R^(m), —SO₂N(R^(l))R^(m), —SCF₃, halo, —CO₂H, and        —CO₂C₁₋₆alkyl; or two R^(k) moieties on adjacent carbon atoms of        attachment together are —OC₁₋₄alkyleneO— to form a cyclic ring        which is unsubstituted or substituted with one or two fluoro        substituents;        -   where R^(l) and R^(m) are each independently —H or            —C₁₋₆alkyl;-   provided that when both R⁴ substituents taken together form a    carbonyl, then R² and R³ taken together are not diazepanyl;    or a pharmaceutically acceptable salt, pharmaceutically acceptable    prodrug, or pharmaceutically active metabolite of such compound.

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, pharmaceuticallyacceptable prodrug, or pharmaceutically active metabolite thereof; and(b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition mediated by histamine H₃ receptor and/or serotonintransporter activity, comprising administering to the subject in need ofsuch treatment an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically active metabolite thereof.

In certain preferred embodiments of the inventive method, the disease,disorder, or medical condition is selected from: cognitive disorders,sleep disorders, psychiatric disorders, and other disorders.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by /), ethyl(Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu),pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that inlight of the ordinary skill in the art and the teachings provided hereinwould be considered equivalent to any one of the foregoing examples.

The term “alkylene” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain, where two hydrogen atomsare removed to for a diradical. Examples of alkylene groups includemethylene (—CH₂—), ethylene, n-propylene, isopropylene, butylene, andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples.

The term “alkenyl” refers to a straight- or branched-chain alkenyl grouphaving from 2 to 12 carbon atoms in the chain. (The double bond of thealkenyl group is formed by two Sp2 hybridized carbon atoms.)Illustrative alkenyl groups include prop-2-phenyl, but-2-phenyl,but-3-phenyl, 2-methylprop-2-phenyl, hex-2-phenyl, and groups that inlight of the ordinary skill in the art and the teachings provided hereinwould be considered equivalent to any one of the foregoing examples.

The term “alkynyl” refers to a straight- or branched-chain alkynyl grouphaving from 2 to 12 carbon atoms in the chain. (The triple bond of thealkynyl group is formed by two sp hybridized carbon atoms.) Illustrativealkynyl groups include ethynyl, propynyl, butynyl, hexynyl, and groupsthat in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, and heterocycloalkyl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any formula given herein is intended to embrace hydrates,solvates, and polymorphs of such compounds, and mixtures thereof.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²⁵I, respectively. Such isotopically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the moiety for the variable appearingelsewhere. In other words, where a variable appears more than once, thechoice of the species from a specified list is independent of the choiceof the species for the same variable elsewhere in the formula.

In preferred embodiments of Formula (I), R^(1b) is

In preferred embodiments, R² and R³ are each independently —H; ormethyl, ethyl, propyl, isopropyl, sec-butyl, 2-methylpropyl,cyclopropyl, cyclobutyl, or cyclopentyl, each unsubstituted orsubstituted as previously described. In further preferred embodiments,R² and R³ are each independently —H, methyl, ethyl, propyl, isopropyl,sec-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-methylaminoethyl,2-dimethylaminoethyl, 2-(cyclopropyl-methyl-amino)-ethyl,2-pyrrolidin-1-yl-ethyl, 2-hydroxy-2-methylpropyl,3-dimethylaminopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. In stillfurther preferred embodiments, R² and R³ are each independently —H,methyl, cyclopropyl, dimethylaminoethyl, or dimethylaminopropyl.

In preferred embodiments, R^(a) and R^(b) are each independently —H,methyl, or cyclopropyl, or R^(a) and R^(b) taken together formpyrrolidinyl.

In alternative embodiments, R² and R³ taken together with the nitrogento which they are attached form azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, homopiperidinyl, diazepanyl,piperazinonyl, or diazepanonyl, each unsubstituted or substituted aspreviously described. In certain preferred embodiments, R² and R³ takentogether with the nitrogen to which they are attached form azetidinyl,3,3-difluoroazetidinyl, pyrrolidinyl, 2-methylpyrrolidinyl,3-hydroxypyrrolidinyl, 3-dimethylaminopyrrolidinyl,2,5-dimethylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl,2-hydroxymethylpyrrolidinyl, 3,3-difluoropyrrolidinyl, piperidinyl,3-fluoropiperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl,4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl,4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro[4,5]dec-8-yl,4-cyanopiperidinyl, 4-carboethoxypiperidinyl, 3-hydroxypiperidinyl,4-hydroxypiperidinyl, 2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl, 4-hydroxymethylpi peridinyl, 3-hydroxyethylpiperidinyl,4-hydroxyethylpiperidinyl, 4-dimethylaminopiperidinyl,4-morpholin-4-yl-piperidin-1-yl, morpholinyl, 2-methylmorpholin-4-yl,3-methylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl,3-hydroxymethylmorpholin-4-yl, 2-hydroxymethylmorpholin-4-yl,piperazinyl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl,4-(2-fluoroethyl)-piperazin-1-yl, 4-isopropyl-piperazin-1-yl,4-cyclopropyl-piperazin-1-yl, 4-cyclobutyl-piperazin-1-yl,4-cyclopentyl-piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,4-(2-methoxyethyl)-piperazin-1-yl,4-(tert-butoxycarbonyl)piperazin-1-yl, 4-phenylpiperazin-1-yl,4-(2-hydroxyphenyl)piperazinyl,4-(4-trifluoromethyl-phenyl)-piperazin-1-yl,4-thiazol-2-yl-piperazin-1-yl, 4-(2-thiophenyl)piperazinyl,4-pyridin-4-yl-piperazin-1-yl, 4-acetylpiperazin-1-yl,4-isobutyryl-piperazin-1-yl, 4-piperazin-2-onyl,1-isopropyl-4-piperazin-2-onyl, 4-isopropyl-1-piperazin-2-onyl,1-cyclopropyl-4-piperazin-2-onyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, 4-isopropyl-[1,4]diazepan-1-yl,4-cyclopropyl-[1,4]diazepan-1-yl, 1-cyclobutyl-4-diazepan-5-onyl,4-isopropyl-1-diazepan-5-onyl, 1-isopropyl-4-diazepan-5-onyl, or1-cyclopropyl-4-diazepan-5-onyl. In further preferred embodiments, R²and R³ taken together with the nitrogen to which they are attached formpyrrolidinyl, 3-dimethylaminopyrrolidinyl, piperidinyl,4-fluoropiperidinyl, 4-dimethylaminopiperidinyl,4-morpholin-4-yl-piperidin-1-yl, morpholinyl, thiomorpholinyl,piperazinyl, 4-methyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl,4-(2-fluoroethyl)-piperazin-1-yl, 4-cyclopropyl-piperazin-1-yl,4-cyclobutyl-piperazin-1-yl, 4-cyclopentyl-piperazin-1-yl,4-pyridin-4-yl-piperazin-1-yl, 4-piperazin-2-onyl,1-isopropyl-4-piperazin-2-onyl, 4-isopropyl-[1,4]diazepan-1-yl, or1-isopropyl-4-diazepan-5-onyl.

In preferred embodiments, each R^(d) moiety is independently selectedfrom the group consisting of: methyl, ethyl, isopropyl, hydroxyethyl,fluoro, methoxy, dimethylamino, piperidinyl, morpholinyl, acetyl,trifluoromethyl, —CO₂H, and —CO₂-methyl.

In preferred embodiments, R^(g) and R^(h) are each independently —H,methyl, ethyl, or isopropyl, or R^(g) and R^(h) taken together withtheir nitrogen of attachment form pyrrolidinyl, piperidinyl, morpolinyl,or thiomorpholinyl.

In preferred embodiments, R^(e) is selected from the group consistingof: —H, methyl, ethyl, isopropyl, 2-fluoroethyl, hydroxyethyl,methoxypropyl, acetyl, tert-butoxycarbonyl, phenyl, 4-pyridyl,cyclopropyl, cyclobutyl, cyclopentyl, and piperidinyl. In furtherpreferred embodiments, R^(e) is selected from the group consisting of:—H, isopropyl, and cyclopropyl.

In preferred embodiments, q is 1 and both R⁴ substituents taken togetherform a carbonyl. In other preferred embodiments, q is 0. In still otherpreferred embodiments, q is 1 and each R⁴ is —H.

In preferred embodiments, Y is —O— or —S—.

In preferred embodiments, Cyc is a phenyl or pyridyl group unsubstitutedor substituted with one, two, or three R^(k) moieties. In furtherpreferred embodiments, Cyc is a thiophenyl, oxazolyl, thiazolyl,pyrazolyl, pyridinyl, or pyrazinyl group unsubstituted or substitutedwith one, two, or three R^(k) moieties.

In further preferred embodiments, Cyc is phenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl,3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,4-ethylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,3-iodophenyl, 4-iodophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2-fluoro-3-chlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl,3-chloro-4-fluorophenyl, 4-fluoro-3-methylphenyl,3-chloro-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl,3-fluoro-4-methoxyphenyl, 3-chloro-4-difluoromethoxyphenyl,4-chloro-3-trifluoromethylphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,4-difluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,3-acetylphenyl, 4-acetylphenyl, 3-nitrophenyl, 4-nitrophenyl,4-aminophenyl, 4-dimethylaminophenyl, 4-carbamoylphenyl,4-methanesulfanylphenyl, 4-methanesulfinylphenyl,4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl,3-methyl-4-methylsulfanylphenyl, benzo[1,3]dioxol-4-yl,benzo[1,3]dioxol-5-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl,thiazol-5-yl, thiazol-2-yl, 2H-pyrazol-3-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 4-trifluoromethyl-pyridin-2-yl, 2,6-dimethyl-pyridin-3-yl,6-methyl-pyridin-3-yl, 2-chloro-5-pyridinyl,2-dimethylamino-5-pyridinyl, 6-methoxy-pyridin-3-yl,6-methylsulfanyl-pyridin-3-yl, 2-hydroxy-5-pyridinyl,6-bromo-pyridin-3-yl, or pyrazin-2-yl.

In certain particular embodiments, Cyc is phenyl, 3-methoxyphenyl,3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3,4-dichlorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 4-trifluoromethylphenyl,4-methanesulfanylphenyl, 3-methyl-4-methanesulfanylphenyl, 2-pyridinyl,3-pyridinyl, or 6-methyl-3-pyridinyl.

In preferred embodiments, each R^(k) moiety is independently selectedfrom the group consisting of: methyl, methoxy, fluoro, chloro,trifluoromethyl, methanesulfanyl, trifluoromethanesulfanyl, cyano, andtrifluoromethoxy.

In preferred embodiments, R^(l) and R^(m) are each independently —H ormethyl.

In preferred embodiments, R⁵ is —H or methyl. In further preferredembodiments, R⁵ is —H.

In preferred embodiments, R⁶ is —H, methyl, ethyl, isopropyl, sec-butyl,cyclopropyl, cyclobutyl, or cyclopentyl, each unsubstituted orsubstituted as previously described. In further preferred embodiments,R⁶ is —H or methyl.

In preferred embodiments, R⁷ is —H, methyl, ethyl, propyl, isopropyl,sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, eachunsubstituted or substituted as previously described. In furtherpreferred embodiments, R⁷ is methyl, ethyl, isopropyl, sec-butyl,cyclopropyl, cyclobutyl, or cyclopentyl. In still further preferredembodiments, R⁷ is methyl, ethyl, isopropyl, or cyclopropyl.

In alternative embodiments, R⁶ and R⁷ taken together with their nitrogenof attachment form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholin-4-yl,homopiperidinyl, diazepanyl, or homomorpholinyl, each unsubstituted orsubstituted as previously described. In further preferred embodiments,R⁶ and R⁷ taken together with their nitrogen of attachment formpiperidinyl, pyrrolidinyl, morpholinyl, 4-isopropyl-piperazin-1-yl, orhomomorpholinyl.

In certain preferred embodiments, the compound of Formula (I) isselected from the group consisting of:

Ex. Compound Name 1[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 2(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone; 3(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone; 4(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone; 5(4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 6(4-Isopropyl-piperazin-1-yl)-[4-(3-methoxy-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 7[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 8[4-(4-Chloro-phenoxy)-3-cyclopropylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 9(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone; 10(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone; 11[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 12(4-Cyclopropyl-piperazin-1-yl)-(3-methylaminomethyl-4-phenoxy-phenyl)-methanone; 13(4-Cyclopropyl-piperazin-1-yl)-[4-(3-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 14(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-phenoxy)-phenyl]-methanone; 15[3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 16(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone; 17[3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 18[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 19(4-Cyclopropyl-piperazin-1-yl)-[4-(4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 20(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-methanone; 21[4-(3-Chloro-4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 22[4-(4-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 23[3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone; 24[4-(3-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 25(S)-3-Dimethylamino-pyrrolidin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone; 264-(3-Chloro-phenoxy)-N-(2-dimethylamino-ethyl)-3-methylaminomethyl-benzamide; 274-(3-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-methylaminomethyl-benzamide; 28[4-(4-Chloro-phenylsulfanyl)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 29(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-2-ylsulfanyl)-phenyl]-methanone; 30[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 31[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 32[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(3-dimethylamino-pyrrolidin-1-yl)-methanone; 33(4-Isopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone; 34(4-Cyclopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone; 35(3-Dimethylamino-pyrrolidin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone; 36[3-(4-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 37[3-(3,4-Dichloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 38[3-(3-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 39(4-Cyclopropyl-piperazin-1-yl)-[3-(3,4-dichloro-phenoxy)-4-methylaminomethyl-phenyl]-methanone 40[5-(4-Isopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 41Methyl-[5-(4-methyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine; 42[5-(4-Cyclobutyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 43Methyl-[2-(4-methylsulfanyl-phenoxy)-5-(4-pyridin-4-yl-piperazin-1-yl)-benzyl]-amine; 44[5-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 45[5-(4-Cyclopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine 46[5-(4-Cyclopropyl-piperazin-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine; 47[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazin-1-yl)-benzyl]-methyl-amine; 481-[3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one; 494-Isopropyl-1-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one; 501-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-4-isopropyl-piperazin-2-one; 51Methyl-[2-(4-methylsulfanyl-phenoxy)-5-(4-morpholin-4-yl-piperidin-1-yl)-benzyl]-amine; 52[5-(4-Isopropyl-[1,4]diazepan-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 53[5-(4-Cyclopropyl-[1,4]diazepan-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 541-Isopropyl-4-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-[1,4]diazepan-5-one; 55[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-[1,4]diazepan-1-yl)-benzyl]-methyl-amine; 56[5-(4-Cyclopropyl-[1,4]diazepan-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine; 571-Cyclopropyl-4-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-[1,4]diazepan-5-one; 58(S)-Dimethyl-{1-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-pyrrolidin-3-yl}-amine; 59(4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-benzyloxy)-3-methylaminomethyl-phenyl]-methanone; 60Cyclopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine; 61[5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 62[5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-dimethyl-amine; 63Ethyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine; 64Isopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine; 655-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzylamine; 664-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-1-isopropyl-piperazin-2-one; 671-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-4-isopropyl-piperazin-2-one; 681-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-4-isopropyl-[1,4]diazepan-5-one; 694-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-1-isopropyl-[1,4]diazepan-5-one; 701-Cyclobutyl-4-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-benzyl]-[1,4]diazepan-5-one; 714-(3-Chloro-phenoxy)-3-methylaminomethyl-N-(2-pyrrolidin-1-yl-ethyl)-benzamide; 72[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone; 734-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-1-isopropyl-[1,4]diazepan-5-one; 74(4-Cyclobutyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 75(4-Cyclopentyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 76[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone; 77[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone; 78[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone; 79(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-pyridin-2-ylsulfanyl)-phenyl]-methanone; 80(4-Cyclopropyl-piperazin-1-yl)-[4-dimethylaminomethyl-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-methanone; 81(3-Benzyloxy-4-dimethylaminomethyl-phenyl)-(4-cyclopropyl-piperazin-1-yl)-methanone; 82[4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 83[3-(2,6-Dimethyl-pyridin-3-yloxy)-4-morpholin-4-ylmethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 84(4-Dimethylaminomethyl-3-phenoxy-phenyl)-piperidin-1-yl- methanone; 85(4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-phenoxy-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone; 86[4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-(pyridin-3-yloxy)-phenyl]-(4-dimethylamino-piperidin-1-yl)-methanone; 87[4-(4-Isopropyl-piperazin-1-ylmethyl)-3-phenoxy-phenyl]-piperidin-1-yl-methanone; 88[4-(4-Isopropyl-piperazin-1-ylmethyl)-3-(pyridin-3-yloxy)-phenyl]-piperidin-1-yl-methanone; 894-Dimethylaminomethyl-N-(2-methylamino-ethyl)-3-(pyridin-3-yloxy)-benzamide; 90N-[2-(Cyclopropyl-methyl-amino)-ethyl]-4-dimethylaminomethyl-3-(pyridin-3-yloxy)-benzamide; and 91[5-(4-Isopropyl-piperazine-1-carbonyl)-2-(3-methoxy-phenoxy)-benzyl]-methyl-carbamic acid tert-butyl ester;and pharmaceutically acceptable salts thereof.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formula (I), preferably of those describedabove and of the specific compounds exemplified herein, and methods oftreatment using such salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. A compound of Formula (I)may possess a sufficiently acidic group, a sufficiently basic group, orboth types of functional groups, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, any compatible mixture ofacids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

If the compound of Formula (I) is an acid, such as a carboxylic acid orsulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as benzylamines, pyrrolidines, piperidine,morpholine, and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum,and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I), and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, ora polypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl)amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl)esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Adv. Drug Delivery Rev. 1996,19,115. Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in J. Med.Chem. 1996, 39, 10. Free amines can also be derivatized as amides,sulfonamides or phosphonamides. All of these prodrug moieties mayincorporate groups including ether, amine, and carboxylic acidfunctionalities.

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula (I), and uses of such metabolites inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini, et al. J. Med. Chem. 1997,40, 2011-2016; Shan, et al. J. Pharm. Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of the present invention are useful as modulators of thehistamine H₃ receptor and/or the serotonin transporter in the methods ofthe invention. Accordingly, the invention relates to methods of usingthe compounds of the invention to treat subjects diagnosed with orsuffering from a disease, disorder, or condition mediated by histamineH₃ receptor and/or serotonin transporter activity, such as thosedescribed herein.

The term “treat” or “treating” as used herein is intended to refer toadministration of a compound or composition of the invention to asubject for the purpose of effecting a therapeutic or prophylacticbenefit through modulation of histamine H₃ receptor and/or the serotonintransporter activity. Treating includes reversing, ameliorating,alleviating, inhibiting the progress of, lessening the severity of, orpreventing a disease, disorder, or condition, or one or more symptoms ofsuch disease, disorder or condition mediated through modulation ofhistamine H₃ receptor and/or the serotonin transporter activity. Theterm “subject” refers to a mammalian patient in need of such treatment,such as a human. “Modulators” include both inhibitors and activators,where “inhibitors” refer to compounds that decrease, prevent,inactivate, desensitize or down-regulate histamine H₃ receptor and/orthe serotonin transporter expression or activity, and “activators” arecompounds that increase, activate, facilitate, sensitize, or up-regulatehistamine H₃ receptor and/or the serotonin transporter expression oractivity.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by histamine H₃ receptor and/orthe serotonin transporter activity, such as: cognitive disorders, sleepdisorders, psychiatric disorders, and other disorders. Symptoms ordisease states are intended to be included within the scope of “medicalconditions, disorders, or diseases.”

Cognitive disorders include, for example, dementia, Alzheimer's disease(Panula, P. et al., Soc. Neurosci. Abstr. 1995, 21, 1977), cognitivedysfunction, mild cognitive impairment (pre-dementia), attention deficithyperactivity disorders (ADHD), attention-deficit disorders, andlearning and memory disorders (Barnes, J. C. et al., Soc. Neurosci.Abstr. 1993, 19, 1813). Learning and memory disorders include, forexample, learning impairment, memory impairment, age-related cognitivedecline, and memory loss. H₃ antagonists have been shown to improvememory in a variety of memory tests, including the elevated plus maze inmice (Miyazaki, S. et al. Life Sci. 1995, 57(23), 2137-2144), atwo-trial place recognition task (Orsetti, M. et al. Behav. Brain Res.2001, 124(2), 235-242), the passive avoidance test in mice (Miyazaki, S.et al. Meth. Find. Exp. Clin. Pharmacol. 1995, 17(10), 653-658) and theradial maze in rats (Chen, Z. Acta Pharmacol. Sin. 2000, 21(10),905-910). Also, in the spontaneously hypertensive rat, an animal modelfor the learning impairments in attention-deficit disorders, H₃antagonists were shown to improve memory (Fox, G. B. et al. Behav. BrainRes. 2002, 131(1-2), 151-161).

Sleep disorders include, for example, insomnia, disturbed sleep,narcolepsy (with or without associated cataplexy), cataplexy, disordersof sleep/wake homeostasis, idiopathic somnolence, excessive daytimesleepiness (EDS), circadian rhythm disorders, fatigue, lethargy, jetlag, and REM-behavioral disorder. Fatigue and/or sleep impairment may becaused by or associated with various sources, such as, for example,sleep apnea, perimenopausal hormonal shifts, Parkinson's disease,multiple sclerosis (MS), depression, chemotherapy, or shift workschedules.

Psychiatric disorders include, for example, schizophrenia (Schlicker, E.and Marr, I., Naunyn-Schmiedeberg's Arch. Pharmacol. 1996, 353,290-294), bipolar disorders, manic disorders, depression (Lamberti, C.et al. Br. J. Pharmacol. 1998, 123(7), 1331-1336; Perez-Garcia, C. etal. Psychopharmacology 1999, 142(2), 215-220) (Also see: Stark, H. etal., Drugs Future 1996, 21(5), 507-520; and Leurs, R. et al., Prog. DrugRes. 1995, 45, 107-165 and references cited therein),obsessive-compulsive disorder, and post-traumatic stress disorder.

Other disorders include, for example, motion sickness, vertigo (e.g.vertigo or benign postural vertigo), epilepsy (Yokoyama, H. et al., Eur.J. Pharmacol. 1993, 234, 129-133), migraine, neurogenic inflammation,eating disorders (Machidori, H. et al., Brain Res. 1992, 590, 180-186),obesity, substance abuse disorders, tinitus, movement disorders (e.g.restless leg syndrome), eye-related disorders (e.g. macular degenerationand retinitis pigmentosis), and sexual dysfunction (including prematureejaculation).

Particularly, as modulators of the histamine H₃ receptor and/or theserotonin transporter, the compounds of the present invention are usefulin the treatment or prevention of depression, disturbed sleep,narcolepsy, fatigue, lethargy, cognitive impairment, memory impairment,memory loss, learning impairment, attention-deficit disorders, andeating disorders.

In a treatment method according to the invention, an effective amount ofa compound according to the invention is administered to a subjectsuffering from or diagnosed as having such a disease, disorder, orcondition. An “effective amount” means an amount or dose sufficient togenerally bring about the desired therapeutic or prophylactic benefit inpatients in need of such treatment.

Effective amounts or doses of the compounds of the present invention maybe ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. An exemplary dose is in the range of from about0.001 to about 200 mg of compound per kg of subject's body weight perday, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day,or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention may be used in combinationwith additional active ingredients in the treatment of the aboveconditions. In an exemplary embodiment, additional active ingredientsare those that are known or discovered to be effective in the treatmentof conditions, disorders, or diseases mediated by histamine H₃ receptorand/or the serotonin transporter activity or that are active againstanother target associated with the particular condition, disorder, ordisease, such as H₁ receptor antagonists, H₂ receptor antagonists, H₃receptor antagonists, topiramate (Topamax™), and neurotransmittermodulators such as serotonin-norepinephrine reuptake inhibitors,selective serotonin reuptake inhibitors (SSRIs), noradrenergic reuptakeinhibitors, non-selective serotonin re-uptake inhibitors (NSSRIs),acetylcholinesterase inhibitors (such as tetrahydroaminoacridine,Donepezil (Aricept™), Rivastigmine, or Galantamine (Reminyl™)), ormodafinil. The combination may serve to increase efficacy (e.g., byincluding in the combination a compound potentiating the potency oreffectiveness of a compound according to the invention), decrease one ormore side effects, or decrease the required dose of the compoundaccording to the invention.

More particularly, compounds of the invention in combination withmodafinil are useful for the treatment of narcolepsy, excessive daytimesleepiness (EDS), Alzheimer's disease, depression, attention-deficitdisorders, MS-related fatigue, post-anesthesia grogginess, cognitiveimpairment, schizophrenia, spasticity associated with cerebral palsy,age-related memory decline, idiopathic somnolence, or jet-lag.Preferably, the combination method employs doses of modafinil in therange of about 20 to 300 mg per dose.

The compounds of the invention are used, alone or in combination withone or more other active ingredients, to formulate pharmaceuticalcompositions of the invention. A pharmaceutical composition of theinvention comprises: (a) an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, pharmaceutically acceptableprodrug, or pharmaceutically active metabolite thereof; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a compound of the invention andthat is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the compounds of the invention may be prepared usingsuitable pharmaceutical excipients and compounding techniques now orlater known or available to those skilled in the art. The compositionsmay be administered in the inventive methods by oral, parenteral,rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil, sesame oil, or olive oil, liquid paraffin, amixture of mono and di-glycerides of short chain fatty acids,polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid compositions may optionally contain: pharmaceutically-acceptableexcipients such as suspending agents (for example, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose,carboxymethylcellulose, aluminum stearate gel and the like); non-aqueousvehicles, e.g., oil (for example, almond oil or fractionated coconutoil), propylene glycol, ethyl alcohol, or water; preservatives (forexample, methyl or propyl p-hydroxybenzoate or sorbic acid); wettingagents such as lecithin; and, if desired, flavoring or coloring agents.

The compounds of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Reactions may be performed between the meltingpoint and the reflux temperature of the solvent, and preferably between0° C. and the reflux temperature of the solvent. Unless otherwisespecified, the variables are as defined above in reference to Formula(I).

Table of Acronyms and Abbreviations Term Acronym or Abbreviationtert-Butoxycarbonyl Boc 1,8-Diazabicyclo[5.4.0]undec-7-ene DBU1,2-Dichloroethane DCE Dichloromethane DCM Diethyl azodicarboxylate DEADDiisopropyl azodicarboxylate DIAD Ethylene glycol dimethyl ether DMEN,N-Dimethylformamide DMF Diethyl ether Et₂O Ethyl acetate EtOAc EthanolEtOH Methanol MeOH Tetrahydrofuran THF Trifluoroacetic acid TFA

Referring to Scheme A, fluorobenzenes A1, where HAL is Br or Cl, arecommercially available or are prepared according to methods known to oneskilled in the art. Aromatic substitution of compounds A1 with reagentsCyc-YH, where Y is —O— or —S—, in the presence of a suitable base suchas K₂CO₃, Na₂CO₃, or Cs₂CO₃, in a solvent such as DMF, DME, or toluene,or a mixture thereof, at temperatures between room temperature and thereflux temperature of the solvent, provides ethers and thioethers A3.Ethers and thioethers A3 are reacted with amines A4 to form benzylamines A5 under reductive amination conditions known to one skilled inthe art. Preferred conditions include a reducing agent such as NaBH₄,NaCNBH₃, or NaBH(OAc)₃, in a solvent such as MeOH, EtOH, or DCE, andwith optional additives such as acetic acid or a Lewis acid. Where aprimary amine H₂NR⁷ is used for the reductive amination, the resultingbenzyl amine may be protected in a subsequent step with a suitablenitrogen protecting group, such as a Boc or other suitable carbamoylgroup, under conditions known to one skilled in the art. Coupling withamines A6 is accomplished using two methods. First, aryl amination withamines A6, in the presence of a palladium catalyst such as (PPh₃)₂PdCl₂or Pd₂(dba)₃, a phosphine ligand such as2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPHOS), and abase such as tBuONa, in a solvent such as DMF, DME, or toluene, attemperatures between room temperature and the reflux temperature of thesolvent, provides anilines A7 (where q is 0). Aminocarbonylation of arylbromides A5 with amines A6 to give amides A7 (where q is 1) may beperformed in the presence of a suitable catalyst, such as Hermann'scatalyst(trans-di-p-acetatobis[2-(di-o-tolylphosphino)benzyl]-dipalladium),coupling aids such as tri-t-butylphosphonium tetrafluoroborate, a COequivalent such as Mo(CO)₆, a suitable base such as DBU, in a solventsuch as THF or toluene, at temperatures between room temperature and150° C. in a microwave reactor. If a nitrogen protecting group is used,removal is accomplished under conditions known in the art, such asacidic or hydrogenation conditions, following the coupling step. Wherethe synthesis provides compounds where Y is —S—, oxidation to thecorresponding sulfoxides and sulfones (Y is —SO— or —SO₂—) may beperformed under conditions known in the art.

Referring to Scheme B, phenols or thiophenols B1 may be converted toamines B2 by reductive amination methods as described in Scheme A.Alkylation of phenols and thiols B2 with CycCH₂X (where X is a suitableleaving group, such as Br, Cl, OTs, or the like), in the presence of asuitable base such as K₂CO₃, Na₂CO₃, NaH, or the like, in a solvent suchas CH₃CN or THF, provides ethers and thioethers A5, where Y is —O— or—S—. In another embodiment, phenols or thiophenols B2 may be reactedunder Mitsunobu conditions with CycCH₂X, where X is OH or SH, in thepresence of PPh₃ and DEAD or DIAD, in a solvent such as CH₃CN or THF, toform ethers and thioethers A5, where Y is —OCH₂—. Aromatic substitutionwith activated CycBr reagents (where Cyc is a suitable heteroaryl group)may be accomplished in the presence of a suitable base such as K₂CO₃,Na₂CO₃, or Cs₂CO₃, in the presence of dehydryating agents such asmolecular sieves or Ca₂O or a mixture thereof, and salicylaldoxime, in asolvent such as DMF, DME, or toluene, or a mixture thereof, attemperatures between room temperature and the reflux temperature of thesolvent, to form ethers or thioethers A5 where where Y is —O— or —S—.All such ethers and thioethers A5 may be processed into compounds ofFormula (I) as described in Scheme A.

Compounds of Formula (I) may also be prepared according to Scheme C. Thecarbonyl functionality of aryl bromides A1 is protected with a suitableprotecting group, such as an acetal or ketal, using methods known in theart. Aldehydes are preferably protected by treatment with ethyleneglycol and a catalyst such as p-toluenesulfonic acid, in a solvent suchas benzene or toluene, preferably at reflux temperature. Removal ofwater is accomplished with molecular sieves or a Dean-Stark trap. Theresulting bromides C1 are converted to benzaldehydes C2 by halogen-metalexchange with an organolithium reagent such as n-BuLi, in a solvent suchas THF or Et₂O, and trapping of the resultant lithium anion with DMF.Reductive amination with amines A6 using methods as described in SchemeA provides benzyl amines C3. Aldehydes C2 may alternatively be reducedto the corresponding benzyl alcohols, activated (e.g., as a benzylchloride, bromide, or tosylate), and displaced with suitable reagents A6to provide benzyl amines C3. The carbonyl group may be deprotected, suchas with 6 N HCl, and subsequent coupling with Cyc-YH and reductiveamination as in Scheme A gives rise to compounds C4. One skilled in theart will recognize that this Scheme may also be accomplished withphenols and thiols rather than fluorobenzenes A1 to access compoundswhere Y is —OCH₂— and where Cyc is a suitable heteroaryl group.

Those skilled in the art will recognize that several of the chemicaltransformations described above may be performed in a different orderthan that depicted in the above Schemes. In addition, one skilled in theart will recognize that compounds of formulae A7 and C4 are compounds ofFormula (I).

Additional applicable methodologies are described in U.S. Pat. Publ. US2006/0194837 A1, U.S. Pat. Publ. US 2006/0293316 A1, and U.S. Pat. Publ.US 2006/0287292 A1.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, amines ofFormula (I) may be treated with trifluoroacetic acid, HCl, or citricacid in a solvent such as Et₂O, DCM, THF, or MeOH to provide thecorresponding salt forms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

The following examples are provided to further illustrate the inventionand various preferred embodiments.

EXAMPLES Chemistry:

Where solutions or mixtures are “concentrated”, they are typicallyconcentrated under reduced pressure using a rotary evaporator.

Normal phase flash column chromatography (FCC) was typically performedwith RediSep® silica gel columns using 2 M NH₃ in MeOH/DCM as eluent,unless otherwise indicated.

Preparative Reversed-Phase high performance liquid chromatography (HPLC)was typically performed using a Gilson® instrument with a YMC-PackODS-A, 5 μm, 75×30 mm column, a flow rate of 25 mL/min, detection at 220and 254 nm, with a 15% to 99% acetonitrile/water/0.05% TFA gradient.

Analytical Reversed-Phase HPLC was typically performed using 1) aHewlett Packard Series 1100 instrument with an Agilent ZORBAX® Bonus RP,5 μm, 4.6×250 mm column, a flow rate of 1 mL/min, detection at 220 and254 nm, with a 1% to 99% acetonitrile/water/0.05% TFA gradient; or 2) aHewlett Packard HPLC instrument with an Agilent ZORBAX® Eclipse XDB-C8,5 μm, 4.6×150 mm column, a flow rate of 1 mL/min, detection at 220 and254 nm, with a 1% to 99% acetonitrile/water/0.05% TFA gradient.

Where trifluoroacetic acid salts were obtained, they were obtained frompreparative reversed-phase HPLC or from deprotection of a Boc group withTFA in a final step. Where hydrochloride salts were obtained, they wereobtained by treatment of a solution of the corresponding free base inDCM with an excess of 2.5 M HCl in MeOH, and concentration of thereaction solution.

In obtaining the characterization data described in the examples below,the following analytical protocols were followed as indicated.

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated. Calculated mass corresponds to the exact mass.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz),DPX500 (500 MHz), DRX600 (600 MHz) spectrometer. The format of the ¹HNMR data below is: chemical shift in ppm down field of thetetramethylsilane reference (multiplicity, coupling constant J in Hz,integration).

Example 1[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

Step A: 5-Bromo-2-(3,4-dichloro-phenoxy)-benzaldehyde. To a solution of5-bromo-2-fluoro-benzaldehyde (5.13 g, 25.4 mmol) in DMF (25 mL) wereadded K₂CO₃ (7.15 g, 51.8 mmol) and 3,4-dichloro-phenol (4.67 g, 28.8mmol). The mixture was heated at 90° C. for 24 h and then was allowed tocool to room temperature (rt). Water was added and the mixture wasextracted with Et₂O. The combined organic layers were dried (MgSO₄) andconcentrated. The residue was diluted with DCM and hexanes and theresulting solids were collected by vacuum filtration to provide thedesired product (4.74 g, 54%). ¹H NMR (CDCl₃): 10.36 (s, 1H), 8.06 (d,J=2.5, 1H), 7.67 (dd, J=8.8, 2.6, 1H), 7.46 (d, J=8.8, 1H), 7.17 (d,J=2.8, 1H), 6.92 (dd, J=8.8, 2.8, 1H), 6.84 (d, J=8.8, 1H).

Step B: [5-Bromo-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine. To amixture of 5-bromo-2-(3,4-dichloro-phenoxy)-benzaldehyde (4.74 g, 13.8mmol) in MeOH (250 mL) was added MeNH₂ (40% aq.; 20 mL, 260 mmol), andthe resulting mixture was stirred at rt until homogeneous. The mixturewas cooled to 0° C. and treated with NaBH₄ (1.05 g, 27.8 mmol)portionwise. After 24 h, the mixture was concentrated and the residuewas diluted with 1 N NaOH and extracted with DCM. The combined organiclayers were dried (Na₂SO₄) and concentrated. The crude product waspurified by FCC to provide the desired product (4.80 g, 97%). MS (ESI):mass calcd. for C₁₄H₁₂BrCl₂NO, 358.95; m/z found, 360.1 [M+H]⁺. ¹H NMR(CDCl₃): 7.61 (d, J=2.5, 1H), 7.40-7.37 (m, 2H), 7.03 (d, J=2.8, 1H),6.82-6.79 (m, 2H), 3.72 (s, 2H), 2.44 (s, 3H), 1.30-1.21 (m, 1H).

Step C: [5-Bromo-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-carbamic acidtert-butyl ester. To a solution of[5-bromo-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine (4.61 g, 12.8mmol) in DCM (250 mL) were added Et₃N (3.6 mL, 25.8 mmol) anddi-tert-butyl dicarbonate (3.44 g, 15.8 mmol). After 1 h, the mixturewas diluted with 1 N NaOH and extracted with DCM. The combined organiclayers were dried (Na₂SO₄) and concentrated. The crude material wascarried forward without purification (6.35 g, >100%). ¹H NMR (CDCl₃):7.47-7.31 (m, 3H), 7.03 (d, J=2.8, 1H), 6.80-6.74 (m, 2H), 4.46-4.32 (m,2H), 2.93-2.78 (m, 3H), 1.45 (br s, 9H).

Step D.[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazine-1-carbonyl)-benzyl]-methyl-carbamicacid tert-butyl ester. To a solution of[5-bromo-2-(3,4-dichloro-phenoxy)-benzyl]-carbamic acid tert-butyl ester(327.0 mg, 0.71 mmol) in THF (2 mL) were added DBU (0.30 mL, 2.0 mmol),1-isopropyl piperazine (0.30 mL, 2.5 mmol), Hermann's catalyst (31.9 mg,0.034 mmol), tri-t-butylphosphium tetrafluoroborate (26.4 mg, 0.091mmol), and Mo(CO)₆ (211.0 mg, 0.80 mmol). After 6 min in a microwavereactor at 125° C., the mixture was cooled to rt and concentrated.Purification by FCC gave the desired product (212.5 mg, 56%).

Step E. To a solution of[2-(3,4-dichloro-phenoxy)-5-(4-isopropyl-piperazine-1-carbonyl)-benzyl]-methyl-carbamicacid tert-butyl ester (212.5 mg, 0.40 mmol) in DCM (2 mL) was added TFA(1 mL). After 30 min, the mixture was concentrated and the residue waspurified by FCC to give the desired product (119.3 mg, 69%). MS (ESI):mass calcd. for C₂₂H₂₇Cl₂N₃O₂, 435.15; m/z found, 436.3 [M+H]⁺. ¹H NMR(CDCl₃): 7.50 (d, J=2.0, 1H), 7.38 (d, J=8.8, 1H), 7.30 (dd, J=8.3, 2.1,1H), 7.06 (d, J=2.8, 1H), 6.88 (d, J=8.3, 1H), 6.82 (dd, J=8.8, 2.8,1H), 3.81-3.69 (m, 4H), 3.53-3.37 (m, 2H), 2.78-2.68 (m, 1H), 2.64-2.43(m, 4H), 2.43 (s, 3H), 1.93 (br s, 1H), 1.04 (d, J=6.5, 6H).

The compounds in Examples 2-27 were prepared by a sequence similar tothat described in Example 1.

Example 2(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₃H₂₉N₃O₂S, 411.20; m/z found, 412.3 [M+H]⁺.¹H NMR (CDCl₃): 7.49 (d, J=2.1, 1H), 7.30-7.26 (m, 3H), 6.94 (d, J=8.7,2H), 6.85 (d, J=8.3, 1H), 3.83 (s, 2H), 3.80-3.68 (m, 2H), 3.51-3.38 (m,2H), 2.72-2.54 (m, 4H), 2.50 (s, 3H), 2.47 (s, 3H), 2.04 (s, 2H),1.68-1.64 (m, 1H), 1.63-1.55 (m, 3H).

Example 3(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₃H₃₁N₃O₂S, 413.21; m/z found, 414.4 [M+H]⁺.¹H NMR (CDCl₃): 7.47 (d, J=2.1, 1H), 7.30-7.24 (m, 3H), 6.93 (d, J=8.8,2H), 6.83 (d, J=8.3, 1H), 3.81 (s, 2H), 3.81-3.70 (m, 2H), 3.56-3.40 (m,2H), 2.77-2.68 (m, 1H), 2.63-2.44 (m, 4H), 2.48 (s, 3H), 2.45 (s, 3H),1.56 (br s, 1H), 1.05 (d, J=6.5, 6H).

Example 4(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone

¹H NMR (CDCl₃): 7.47 (d, J=2.0, 1H), 7.26 (dd, J=8.3, 2.1, 1H), 7.17 (d,J=9.3, 1H), 6.84-6.80 (m, 3H), 3.83 (s, 2H), 3.82-3.70 (m, 2H),3.56-3.41 (m, 2H), 2.77-2.70 (m, 1H), 2.64-2.47 (m, 4H), 2.46 (s, 3H),2.45 (s, 3H), 2.34 (s, 3H), 2.04 (br s, 1H), 1.05 (d, J=6.5, 6H).

Example 5(4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₅Cl₂N₃O₂, 433.13; m/z found, 434.2[M+H]⁺. ¹H NMR (CDCl₃): 7.51 (d, J=2.0, 1H), 7.38 (d, J=8.8, 1H), 7.30(dd, J=8.3, 2.1, 1H), 7.06 (d, J=2.8, 1H), 6.88 (d, J=8.3, 1H), 6.83(dd, J=8.8, 2.8, 1H), 3.79-3.63 (m, 4H), 3.50-3.31 (m, 2H), 2.75-2.50(m, 4H), 2.44 (s, 3H), 1.99 (br s, 1H), 1.67-1.60 (m, 1H), 0.50-0.38 (m,4H).

Example 6(4-Isopropyl-piperazin-1-yl)-[4-(3-methoxy-phenoxy)-3-methylaminomethyl-phenyl]-methanone

¹H NMR (CDCl₃): 7.47 (d, J=2.1, 1H), 7.29-7.21 (m, 2H), 6.89 (d, J=8.3,1H), 6.70-6.66 (m, 1H), 6.57-6.53 (m, 2H), 3.83 (s, 2H), 3.79 (s, 3H),3.55-3.44 (m, 1H), 2.77-2.69 (m, 1H), 2.64-2.47 (m, 3H), 2.46 (s, 3H),1.75-1.63 (m, 5H), 1.05 (d, J=6.5, 6H).

Example 7[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

¹H NMR (CDCl₃): 7.51 (d, J=2.1, 1H), 7.32 (d, J=8.9, 2H), 7.30-7.26 (m,1H), 6.93 (d, J=8.9, 2H), 6.86 (d, J=8.3, 1H), 3.83 (s, 2H), 3.83-3.68(m, 2H), 3.59-3.40 (m, 2H), 2.78-2.72 (m, 1H), 2.66-2.47 (m, 4H), 2.47(s, 3H), 1.75 (br s, 1H), 1.07 (d, J=6.5, 6H).

Example 8[4-(4-Chloro-phenoxy)-3-cyclopropylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₄H₃₀ClN₃O₂, 427.20; m/z found, 428.3 [M+H]⁺.¹H NMR (CDCl₃): 7.48 (d, J=2.0, 1H), 7.33-7.24 (m, 3H), 6.92 (d, J=9.3,2H), 6.84 (d, J=8.3, 1H), 3.89 (s, 2H), 3.83-3.42 (m, 4H), 2.78-2.69 (m,1H), 2.63-2.43 (m, 4H), 2.15-2.09 (m, 1H), 1.05 (d, J=6.5, 6H),0.45-0.34 (m, 4H).

Example 9(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₈N₄O₂, 368.22; m/z found, 369.4 [M+H]⁺.

¹H NMR (MeOD): 8.90-8.86 (m, 1H), 8.74 (d, J=5.3, 1H), 8.39-8.35 (m,1H), 8.12-8.07 (m, 1H), 7.84 (d, J=1.9, 1H), 7.67 (dd, J=8.5, 2.0, 1H),7.23 (d, J=8.5, 1H), 4.98-4.58 (m, 1H), 4.42 (s, 2H), 4.27-3.96 (m, 1H),3.74-3.96 (m, 1H), 3.74-3.35 (m, 5H), 3.30-3.22 (m, 2H), 2.84 (s, 3H),1.41 (d, J=6.7, 6H).

Example 10(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₁H₂₆N₄O₂, 366.21; m/z found, 367.4 [M+H]⁺.¹H NMR (MeOD): 8.83 (s, 1H), 8.71 (d, J=5.1, 1H), 8.30-8.26 (m, 1H),8.04-8.00 (m, 1H), 7.82 (d, J=2.1, 1H), 7.60 (dd, J=8.5, 2.1, 1H), 7.20(d, J=8.5, 1H), 4.42 (s, 2H), 4.18-3.65 (m, 2H), 3.62-3.48 (m, 4H),2.99-2.88 (m, 1H), 2.84 (s, 3H), 1.43 (d, J=12.7, 3H), 1.15-1.11 (m,2H), 1.02-0.97 (m, 2H).

Example 11[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₆ClN₃O₂, 399.17; m/z found, 400.3 [M+H]⁺.¹H NMR (CDCl₃): 7.68 (d, J=2.0, 1H), 7.40-7.34 (m, 2H), 7.26-7.23 (m,1H), 7.08 (t, J=2.1, 1H), 6.96 (ddd, J=8.2, 2.3, 0.92, 1H), 6.82 (d,J=8.5, 1H), 4.32-4.27 (m, 2H), 4.18-2.98 (m, 7H), 2.79 (s, 3H),2.57-2.49 (m, 1H), 1.27-1.19 (m, 3H), 0.93-0.82 (m, 2H).

Example 12(4-Cyclopropyl-piperazin-1-yl)-(3-methylaminomethyl-4-phenoxy-phenyl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₇N₃O₂, 365.21; m/z found, 366.3 [M+H]⁺.¹H NMR (CDCl₃): 7.48 (d, J=2.1, 1H), 7.38-7.33 (m, 2H), 7.28-7.25 (m,1H), 7.16-7.11 (m, 1H), 7.01-6.97 (m, 2H), 6.85 (d, J=8.3, 1H), 3.83 (s,2H), 3.81-3.66 (m, 2H), 3.52-3.38 (m, 2H), 2.74-2.52 (m, 4H), 2.45 (s,3H), 1.68-1.62 (m, 1H), 0.51-0.46 (m, 2H), 0.46-0.40 (m, 2H).

Example 13(4-Cyclopropyl-piperazin-1-yl)-[4-(3-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₆FN₃O₂, 383.20; m/z found, 384.40 [M+H]⁺.¹H NMR (CDCl₃): 7.54 (d, J=2.2, 1H), 7.33-7.27 (m, 2H), 6.91 (d, J=8.4,1H), 6.87-6.81 (m, 1H), 6.80-6.76 (m, 1H), 6.72 (tt, J=10.0, 2.4, 1H),3.86 (br s, 2H), 3.81-3.64 (m, 2H), 3.55-3.32 (m, 2H), 2.75-2.50 (m,4H), 2.48 (s, 3H), 1.70-1.59 (m, 1H), 0.52-0.38 (m, 4H).

Example 14(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-phenoxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₃H₂₆F₃N₃O₂, 433.20; m/z found, 434.4 [M+H]⁺.¹H NMR (CDCl₃): 7.64-7.56 (m, 2H), 7.56-7.52 (m, 1H), 7.32 (dd, J=8.2,2.2, 1H), 7.06-7.01 (m, 2H), 6.94 (d, J=8.2, 1H), 3.83-3.63 (m, 4H),3.54-3.33 (m, 2H), 2.78-2.50 (m, 4H), 2.44 (s, 3H), 1.78-1.56 (m, 1H),0.54-0.38 (m, 4H).

Example 15[3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₃H₂₈N₄O₂, 392.22; m/z found, 393.4 [M+H]⁺.¹H NMR (MeOD): 8.82 (d, J=2.5, 1H), 8.68 (d, J=5.4, 1H), 8.30 (dd,J=8.7, 1.6, 1H), 8.05-8.01 (m, 1H), 7.80 (d, J=1.9, 1H), 7.62 (dd,J=8.5, 2.0, 1H), 7.18 (d, J=8.5, 1H), 4.48 (s, 2H), 4.00-3.31 (m, 6H),2.89-2.80 (m, 2H), 1.38 (d, J=12.8, 2H), 1.10-1.05 (m, 2H), 0.96-0.86(m, 6H).

Example 16(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₄H₃₁N₃O₂S, 425.21; m/z found, 426.4 [M+H]⁺.¹H NMR (CDCl₃): 7.47 (d, J=2.1, 1H), 7.27-7.24 (m, 2H), 7.19-7.16 (m,1H), 6.84-6.81 (m, 3H), 3.83 (s, 2H), 3.80-3.86 (m, 2H), 3.53-3.33 (m,2H), 2.74-2.51 (m, 4H), 2.47-2.46 (m, 3H), 2.45 (s, 3H), 2.34 (s, 3H),1.89-1.80 (m, 3H), 1.68-1.61 (m, 1H).

Example 17[3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₃H₃₀N₄O₂, 394.24; m/z found, 395.4 [M+H]⁺.¹H NMR (CDCl₃): 8.83 (br s, 1H), 8.70 (br s, 1H), 8.27-8.24 (m, 1H),8.03-7.98 (m, 1H), 7.85-7.83 (m, 1H), 7.67 (dd, J=8.5, 2.0, 1H), 7.20(d, J=8.5, 1H), 4.91-4.65 (m, 1H), 4.53 (s, 2H), 4.24-3.95 (m, 1H),3.70-3.38 (m, 5H), 3.28-3.19 (m, 2H), 2.91-2.85 (m, 1H), 1.42 (d, J=6.6,6H), 1.00-0.90 (m, 4H).

Example 18[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₆ClN₃O₂, 399.17; m/z found, 400.3 [M+H]⁺.¹H NMR (CDCl₃): 7.48 (d, J=2.1, 1H), 7.32-7.26 (m, 3H), 6.94-6.90 (m,2H), 6.85 (d, J=8.3, 1H), 3.80 (s, 2H), 3.78-3.66 (m, 2H), 3.53-3.37 (m,2H), 2.76-2.51 (m, 4H), 2.45 (s, 3H), 1.78-1.69 (m, 1H), 1.68-1.62 (m,1H), 0.52-0.40 (m, 4H).

Example 19(4-Cyclopropyl-piperazin-1-yl)-[4-(4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₆FN₃O₂, 383.20; m/z found, 384.4 [M+H]⁺.¹H NMR (CDCl₃): 7.47 (d, J=2.0, 1H), 7.25 (dd, J=8.4, 2.1, 1H),7.08-7.02 (m, 2H), 6.99-6.94 (m, 2H), 6.78 (d, J=8.4, 1H), 3.83 (s, 2H),3.80-3.65 (m, 2H), 3.54-3.36 (m, 2H), 2.72-2.52 (m, 4H), 2.46 (s, 3H),1.76-1.69 (m, 1H), 1.67-1.61 (m, 1H), 0.51-0.39 (m, 4H).

Example 20(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₈N₄O₂, 380.22; m/z found, 381.4 [M+H]⁺.¹H NMR (CDCl₃): 8.29 (d, J=2.8, 1H), 7.51 (d, J=2.1, 1H), 7.27 (dd,J=8.3, 2.2, 1H), 7.21 (dd, J=8.5, 2.8, 1H), 7.15 (d, J=8.4, 1H), 6.80(d, J=8.3, 1H), 3.87 (s, 2H), 3.80-3.63 (m, 2H), 3.52-3.33 (m, 2H),2.73-2.57 (m, 3H), 2.56 (s, 3H), 2.48 (s, 3H), 2.31-2.20 (m, 1H),1.68-1.62 (m, 1H), 0.51-0.40 (m, 4H).

Example 21[4-(3-Chloro-4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₅ClFN₃O₂, 417.16; m/z found, 418.3[M+H]⁺. ¹H NMR (CDCl₃): 7.51 (d, J=2.1, 1H), 7.29 (dd, J=8.3, 2.2, 1H),7.12 (t, J=8.6, 1H), 7.07-7.05 (m, 1H), 6.91-6.86 (m, 1H), 6.83 (d,J=8.3, 1H), 3.85 (s, 2H), 3.83-3.66 (m, 2H), 3.54-3.35 (m, 2H),2.75-2.56 (m, 4H), 2.48 (s, 3H), 2.06-1.90 (m, 1H), 1.69-1.62 (m, 1H),0.52-0.40 (m, 4H).

Example 22[4-(4-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₅ClFN₃O₂, 417.16; m/z found, 418.3[M+H]⁺. ¹H NMR (CDCl₃): 7.49 (d, J=2.0, 1H), 7.28-7.21 (m, 2H),7.15-7.10 (m, 1H), 7.02 (t, J=8.6, 1H), 6.72 (d, J=8.3, 1H), 3.91 (s,2H), 3.80-3.63 (m, 2H), 3.54-3.34 (m, 2H), 2.74-2.52 (m, 4H), 2.48 (s,3H), 2.14-1.96 (m, 1H), 1.67-1.61 (m, 1H), 0.51-0.40 (m, 4H).

Example 23[3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₅H₃₃N₃O₃S, 455.22; m/z found, 456.4 [M+H]⁺.¹H NMR (CDCl₃): 7.41 (d, J=1.9, 1H), 7.22-7.16 (m, 3H), 6.87 (d, J=8.7,2H), 6.75 (d, J=8.4, 1H), 4.73-4.46 (m, 1H), 3.79 (s, 2H), 3.67-3.60 (m,4H), 3.12-2.66 (m, 4H), 2.50-2.44 (m, 4H), 2.42-2.33 (m, 7H), 1.98-1.65(m, 2H), 1.52-1.26 (m, 2H).

Example 24[4-(3-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₅ClFN₃O₂, 417.16; m/z found, 418.3[M+H]⁺. ¹H NMR (CDCl₃): 7.49 (d, J=2.1, 1H), 7.26 (dd, J=8.3, 2,2, 1H),7.24-7.19 (m, 1H), 7.06 (td, J=8.2, 1.8, 1H), 6.96-6.91 (m, 1H), 6.76(d, J=8.3, 1H), 3.88 (s, 2H), 3.82-3.65 (m, 2H), 3.53-3.33 (m, 2H),2.73-2.50 (m, 4H), 2.47 (s, 3H), 1.72 (br s, 1H), 1.68-1.61 (m, 1H),0.51-0.40 (m, 4H).

Example 25(S)-(3-Dimethylamino-pyrrolidin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₉N₃O₂S, 399.20; m/z found, 400.3 [M+H]⁺.¹H NMR (CDCl₃): 7.60 (s, 1H), 7.37 (dd, J=8.4, 2.1, 1H), 7.27 (d, J=7.2,2H), 6.94 (t, J=7.7, 2H), 6.82 (d, J=8.4, 1H), 3.94-3.77 (m, 3H),3.67-3.48 (m, 2H), 3.44-3.31 (m, 1H), 2.79-2.63 (m, 1H), 2.48 (s, 3H),2.44 (s, 3H), 2.32-2.25 (m, 4H), 2.24-2.04 (m, 4H), 1.89-1.76 (m, 1H).

Example 264-(3-Chloro-phenoxy)-N-(2-dimethylamino-ethyl)-3-methylaminomethyl-benzamide

MS (ESI): mass calcd. for C₁₉H₂₄ClN₃O₂, 361.16; m/z found, 362.7 [M+H]⁺.¹H NMR (CDCl₃): 7.89 (d, J=2.2, 1H), 7.71 (dd, J=8.5, 2.3, 1H),7.28-7.24 (m, 1H), 7.12-7.09 (m, 1H), 6.97 (t, J=2.2, 1H), 6.91-6.85 (m,2H), 3.82 (s, 2H), 3.56-3.51 (m, 2H), 2.56 (t, J=5.9, 2H), 2.46 (s, 3H),2.30 (s, 6H).

Example 274-(3-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-methylaminomethyl-benzamide

MS (ESI): mass calcd. for C₂₀H₂₆ClN₃O₂, 375.17; m/z found, 376.7 [M+H]⁺.¹H NMR (CDCl₃): 8.50-8.44 (m, 1H), 7.86 (d, J=2.2, 1H), 7.67 (dd, J=8.5,2.3, 1H), 7.28-7.24 (m, 1H), 7.12-7.08 (m, 1H), 6.97 (d, J=2.2, 1H),6.90-6.84 (m, 2H), 3.81 (s, 2H), 3.59-3.54 (m, 2H), 2.52 (t, J=5.8, 2H),2.43 (s, 3H), 2.31 (s, 6H), 1.80-1.74 (m, 2H).

Example 28[4-(4-Chloro-phenylsulfanyl)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

The title compound was prepared in an similar manner as Example 1, using[5-bromo-2-(4-chloro-phenylsulfanyl)-benzyl]-methyl-carbamic acidtert-butyl ester. MS (ESI): mass calcd. for C₂₂H₂₆ClN₃OS, 415.15; m/zfound, 416.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.47-7.45 (m, 1H), 7.32-7.28 (m,2H), 7.26-7.22 (m, 2H), 7.21-7.16 (m, 2H), 3.87 (s, 2H), 3.79-3.67 (m,2H), 3.45-3.33 (m, 2H), 2.73-2.62 (m, 2H), 2.59-2.50 (m, 2H), 2.46 (s,3H), 1.67-1.60 (m, 2H), 0.56-0.40 (m, 4H).

Example 29(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-2-ylsulfanyl)-phenyl]-methanone

The title compound was prepared by a sequence similar to that describedin Example 28. MS (ESI): mass calculated for C₂₁H₂₆N₄OS, 382.18; m/zfound, 383.7 [M+H]⁺. ¹H NMR (CDCl₃): 8.44-8.41 (m, 1H), 7.61 (d, J=7.9,1H), 7.59-7.58 (m, 1H), 7.49 (td, J=7.6, 1.9, 1H), 7.32 (dd, J=7.9, 1.9,1H), 7.06-7.02 (m, 1H), 6.91-6.88 (m, 1H), 3.90 (s, 2H), 3.80-3.70 (m,2H), 3.46-3.35 (m, 2H), 2.75-2.63 (m, 2H), 2.61-2.53 (m, 2H), 2.41 (s,3H), 1.68-1.62 (m, 1H), 0.50-0.40 (m, 4H).

Example 30[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

Step A: 4-Bromo-2-(pyridin-3-yloxy)-benzaldehyde. The title compound wasprepared in a similar manner as in Example 1, Step A (2.85 g, 71%). MS(ESI): mass calcd. for C₁₂H₈BrNO₂, 276.97; m/z found, 278.0, 280.0[M+H]⁺. ¹H NMR (CDCl₃): 10.47 (s, 1H), 8.53 (dd, J=4.5, 1.3, 1H), 8.51(d, J=2.7, 1H), 7.83 (d, J=8.4, 1H), 7.45-7.42 (m, 1H), 7.42-7.38 (m,2H), 7.02-7.01 (m, 1H).

Step B: [4-Bromo-2-(pyridin-3-yloxy)-benzyl]-cyclopropyl-amine. To amixture of 4-bromo-2-(pyridin-3-yloxy)-benzaldehyde (2.0 g, 7.19 mmol)in DCE (75 mL) were added cyclopropylamine (0.50 mL, 7.2 mmol), aceticacid (2.16 mL, 36.0 mmol), and NaBH(OAc)₃ (95%; 3.62 g, 18.0 mmol)portionwise. After 18 h, the mixture was diluted with 50 mL DCM andwashed with 1 M NaOH (2×25 mL). The organic layer was dried (Na₂SO₄) andconcentrated. FCC purification (EtOAc/DCM) gave the desired product(1.74 g, 76%). MS (ESI): mass calcd. for C₁₅H₁₅BrN₂O, 318.04; m/z found,319.1, 321.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.42-8.39 (m, 2H), 7.31-7.26 (m,4H), 7.00-6.99 (m, 1H), 3.84 (s, 2H), 2.11-2.07 (m, 1H), 0.43-0.40 (m,2H), 0.36-0.33 (m, 2H).

Step C: [4-Bromo-2-(pyridin-3-yloxy)-benzyl]-cyclopropyl-carbamic acidtert-butyl ester. The title compound was prepared in a similar manner asin Example 1, Step C. The crude material was carried forward withoutpurification. MS (ESI): mass calcd. for C₂₀H₂₃BrN₂O₃, 418.09; m/z found,419.1, 421.1 [M+H]⁺.

Step D:Cyclopropyl-[4-(4-isopropyl-piperazine-1-carbonyl)-2-(pyridin-3-yloxy)-benzyl]-carbamicacid tert-butyl ester. The title compound was prepared in a similarmanner as in Example 1, Step D. FCC purification (EtOAc/MeOH/DCM) gavethe desired product. MS (ESI): mass calcd. for C₂₈H₃₈N₄O₄, 494.29; m/zfound, 495.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.40 (m, 1H), 8.40-8.38 (m,1H), 7.31-7.23 (m, 3H), 7.20-7.17 (m, 1H), 6.91-6.89 (m, 1H), 4.53 (s,2H), 3.76-3.70 (m, 2H), 3.43-3.36 (m, 2H), 2.75-2.68 (m, 1H), 2.59-2.48(m, 3H), 2.45-2.38 (m, 2H), 1.44 (s, 9H), 1.03 (d, J=6.5, 6H), 0.72-0.60(m, 4H).

Step E. The title compound was prepared in a similar manner as inExample 1, Step E (66.4 mg, 51%). MS (ESI): mass calcd. for C₂₃H₃₀N₄O₂,394.24; m/z found, 395.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.42-8.40 (m, 1H), 8.39(t, J=3.1, 1H), 7.46 (d, J=7.7, 1H), 7.29-7.27 (m, 2H), 7.18 (dd, J=7.7,1.5, 1H), 6.91 (d, J=1.4, 1H), 3.90 (s, 2H), 3.73 (br s, 2H), 3.39 (brs, 2H), 2.74-2.68 (m, 1H), 2.59-2.55 (m, 2H), 2.45-2.37 (m, 2H),2.14-2.10 (m, 1H), 1.03 (d, J=6.5, 6H), 0.44-0.40 (m, 2H), 0.38-0.34 (m,2H).

The compounds in Examples 31-32 were prepared by a sequence similar tothat described in Example 30.

Example 31[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₃H₂₈N₄O₂, 392.22; m/z found, 393.2 [M+H]⁺.¹H NMR (CDCl₃): 8.42-8.41 (m, 1H), 8.40-8.38 (m, 1H), 7.47 (d, J=7.7,1H), 7.29-7.27 (m, 2H), 7.19-7.17 (m, 1H), 6.92-6.91 (m, 1H), 3.91 (s,2H), 3.69 (br s, 2H), 3.34 (brs, 2H), 2.65 (brs, 2H), 2.50 (brs, 2H),2.15-2.11 (m, 1H), 1.64-1.59 (m, 1H), 0.49-0.36 (m, 8H).

Example 32[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(3-dimethylamino-pyrrolidin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₈N₄O₂, 380.22; m/z found, 381.2 [M+H]⁺.¹H NMR (CDCl₃, mixture of rotamers): 8.41-8.37 (m, 2H), 7.46 (dd, J=7.8,2.4, 1H), 7.31-7.27 (m, 3H), 7.03-7.01 (m, 1H), 3.92-3.74 (m, 3H),3.60-3.20 (m, 3H), 2.74-2.60 (m, 1H), 2.28 (s, 3H), 2.20 (s, 3H),2.18-1.90 (m, 3H), 1.84-1.75 (m, 1H), 0.45-0.34 (m, 4H).

Example 33(4-Isopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone

Step A: 3-(5-Bromo-2-piperidin-1-ylmethyl-phenoxy)-pyridine. The titlecompound was prepared in a similar manner as in Example 30, Step B (0.91g, 85%). MS (ESI): mass calcd. for C₁₇H₁₉BrN₂O, 346.07; m/z found,347.1, 349.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.36 (m, 2H), 7.42 (d, J=8.2,1H), 7.32 (dd, J=8.2, 1.9, 1H), 7.30-7.26 (m, 1H), 7.23-7.20 (m, 1H),7.06 (d, J=1.9, 1H), 3.46 (s, 2H), 2.38 (br s, 4H), 1.55-1.48 (m, 4H),1.44-1.37 (m, 2H).

Step B. The title compound was prepared in a similar manner as inExample 1, Step D. MS (ESI): mass calcd. for C₂₅H₃₄N₄O₂, 422.27; m/zfound, 423.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.36-8.32 (m, 2H), 7.56 (d, J=7.8,1H), 7.25-7.17 (m, 3H), 6.94-6.92 (m, 1H), 3.73 (br s, 2H), 3.49 (s,2H), 3.40 (br s, 2H), 2.73-2.66 (m, 1H), 2.61-2.34 (m, 8H), 1.52-1.46(m, 4H), 1.42-1.35 (m, 2H), 1.02 (d, J=6.5, 6H).

The compounds in Examples 34-35 were prepared by a sequence similar tothat described in Example 33.

Example 34(4-Cyclopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₅H₃₂N₄O₂, 420.25; m/z found, 421.3 [M+H]⁺.¹H NMR (CDCl₃): 8.36 (d, J=2.8, 1H), 8.34 (dd, J=4.6, 1.3, 1H), 7.57 (d,J=7.8, 1H), 7.26-7.18 (m, 3H), 6.94 (d, J=1.4, 1H), 3.70 (br s, 2H),3.50 (s, 2H), 3.36 (br s, 2H), 2.66 (br s, 2H), 2.52 (br s, 2H),2.42-2.33 (m, 4H), 1.65-1.60 (m, 1H), 1.53-1.48 (m, 4H), 1.43-1.36 (m,2H), 0.49-0.40 (m, 4H).

Example 35(3-Dimethylamino-pyrrolidin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone

MS (ESI): mass calcd. for C₂₄H₃₂N₄O₂, 408.25; m/z found, 409.3 [M+H]⁺.¹H NMR (CDCl₃, mixture of rotamers): 8.35-8.32 (m, 2H), 7.57-7.54 (m,1H), 7.33-7.30 (m, 1H), 7.24-7.16 (m, 2H), 7.04 (dd, J=5.6, 1.2, 1H),3.90-3.74 (m, 1H), 3.59-3.51 (m, 1.5H), 3.50 (s, 1H), 3.48 (s, 1H),3.46-3.34 (m, 1H), 3.24 (t, J=9.5, 0.5H), 2.73-2.60 (m, 1H), 2.45-2.30(m, 4H), 2.27 (s, 3H), 2.19 (s, 3H), 2.08-2.01 (m, 1H), 1.83-1.75 (m,1H), 1.52-1.45 (m, 4H), 1.41-1.34 (m, 2H).

The compounds in Examples 36-39 were prepared by a sequence similar tothat described in Example 30.

Example 36[3-(4-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₈ClN₃O₂, 401.19; m/z found, 402.8 [M+H]⁺.¹H NMR (CDCl₃): 7.44 (d, J=7.7, 1H), 7.29 (d, J=8.9, 2H), 7.15 (dd,J=7.7, 1.5, 1H), 6.91 (d, J=8.9, 2H), 6.87 (d, J=1.4, 1H), 3.79 (s, 2H),3.76-3.67 (m, 2H), 3.42-3.32 (m, 2H), 2.73-2.67 (m, 1H), 2.58-2.50 (m,2H), 2.44 (s, 3H), 2.42-2.34 (m, 2H), 1.02 (d, J=6.5, 6H).

Example 37[3-(3,4-Dichloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₇Cl₂N₃O₂, 435.15; m/z found, 436.7[M+H]⁺. ¹H NMR (CDCl₃): 7.46 (d, J=7.8, 1H), 7.37 (d, J=8.8, 1H), 7.19(dd, J=7.7, 1.5, 1H), 7.05 (d, J=2.8, 1H), 6.90 (d, J=1.5, 1H), 6.81(dd, J=8.8, 2.8, 1H), 3.77-3.66 (m, 4H), 3.44-3.33 (m, 2H), 2.74-2.66(m, 1H), 2.58-2.50 (m, 2H), 2.45-2.35 (m, 5H), 1.02 (d, J=6.6, 6H).

Example 38[3-(3-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): mass calcd. for C₂₂H₂₈ClN₃O₂, 401.19; m/z found, 402.8 [M+H]⁺.¹H NMR (CDCl₃): 7.47 (d, J=7.7, 1H), 7.27 (t, J=8.1, 1H), 7.19 (dd,J=7.7, 1.5, 1H), 7.11-7.07 (m, 1H), 6.97 (t, J=2.2, 1H), 6.91 (d, J=1.5,1H), 6.86 (ddd, J=8.3, 2.3, 0.82, 1H), 3.81 (s, 2H), 3.77-3.67 (m, 2H),3.45-3.33 (m, 2H), 2.76-2.67 (m, 1H), 2.60-2.50 (m, 2H), 2.47-2.36 (m,5H), 1.03 (d, J=6.5, 6H).

Example 39(4-Cyclopropyl-piperazin-1-yl)-[3-(3,4-dichloro-phenoxy)-4-methylaminomethyl-phenyl]-methanone

MS (ESI): mass calcd. for C₂₂H₂₅Cl₂N₃O₂, 433.13; m/z found, 434.7[M+H]⁺. ¹H NMR (CDCl₃): 7.48 (d, J=7.7, 1H), 7.39 (d, J=8.8, 1H), 7.20(dd, J=7.7, 1.5, 1H), 7.08 (d, J=2.8, 1H), 6.92 (d, J=1.5, 1H), 6.83(dd, J=8.8, 2.8, 1H), 3.80 (s, 2H), 3.76=3.63 (m, 2H), 3.42-3.27 (m,2H), 2.71-2.60 (m, 2H), 2.58-2.47 (m, 2H), 2.46 (s, 3H), 1.66-1.59 (m,1H), 0.51-0.38 (m, 4H).

Example 40[5-(4-Isopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine

Step A:[5-(4-Isopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-carbamicacid tert-butyl ester. A mixture of[5-bromo-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-carbamic acidtert-butyl ester (300 mg, 0.684 mmol) {prepared in an analogous fashionto Example 1, Steps A-C}, isopropyl piperazine (132 mg, 1.02 mmol),XPHOS (39 mg, 0.082 mmol), Pd₂(dba)₃ (62.6 mg, 0.0684 mmol), and t-BuONa(98.0 mg, 1.02 mmol) in toluene was heated in a sealed tube overnight at120° C. After cooling to rt, the mixture was filtered throughdiatomaceous earth and the filtrate was concentrated. Purification byFCC gave the desired product (180 mg, 54%). MS (ESI): mass calcd. forC₂₇H₃₉N₃O₃S, 485.27; m/z found, 486.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.22 (d,J=8.5, 2H), 6.86-6.83 (m, 1H), 6.83-6.80 (m, 4H), 4.42-4.35 (m, 2H),3.19-3.16 (m, 4H), 2.87-2.83 (m, 2H), 2.80-2.75 (m, 1H), 2.75-2.71 (m,1H), 2.71-2.67 (m, 4H), 2.44 (s, 3H), 1.48-1.40 (m, 9H), 1.10 (d, J=6.5,6H).

Step B. The title compound was prepared in an analogous fashion toExample 1, Step E. MS (ESI): mass calcd. for C₂₂H₃₁N₃OS, 385.22; m/zfound, 386.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.22 (d, J=8.9, 2H), 6.99 (d,J=2.7, 1H), 6.86-6.80 (m, 4H), 3.69 (s, 2H), 3.22-3.17 (m, 4H),2.72-2.67 (m, 4H), 2.45 (s, 3H), 2.40 (s, 3H), 2.08-1.97 (br s, 1H),1.10 (d, J=6.5, 6H).

The compounds in Examples 41-58 were prepared by a sequence similar tothat described in Example 40.

Example 41Methyl-[5-(4-methyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine

MS (ESI): mass calcd. for C₂₀H₂₇N₃OS, 357.19; m/z found, 358.3 [M+H]⁺.¹H NMR (CDCl₃): 7.22 (d, J=8.9, 2H), 7.01 (d, J=2.5, 1H), 6.85-6.81 (m,4H), 3.78 (s, 2H), 3.20-3.16 (m, 4H), 2.59-2.56 (m, 4H), 2.45 (s, 3H),2.44 (s, 3H), 2.35 (s, 3H).

Example 42[5-(4-Cyclobutyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₃H₃₁N₃OS, 397.22; m/z found, 398.4 [M+H]⁺.¹H NMR (CDCl₃): 7.21 (d, J=8.8, 2H), 6.97 (d, J=2.8, 1H), 6.84-6.76 (m,4H), 3.68 (s, 2H), 3.20-3.16 (m, 4H), 2.82-2.74 (m, 1H), 2.50-2.46 (m,4H), 2.43 (s, 3H), 2.39 (s, 3H), 2.09-2.02 (m, 2H), 1.96-1.86 (m, 2H),1.78-1.66 (m, 2H).

Example 43Methyl-[2-(4-methylsulfanyl-phenoxy)-5-(4-pyridin-4-yl-piperazin-1-yl)-benzyl]-amine

MS (ESI): mass calcd. for C₂₄H₂₈N₄OS, 420.20; m/z found, 421.3 [M+H]⁺.¹H NMR (CDCl₃): 8.42-8.21 (m, 2H), 7.24 (d, J=8.8, 2H), 7.09-7.05 (m,1H), 6.92-6.82 (m, 4H), 6.78-6.66 (m, 2H), 3.80-3.67 (m, 2H), 3.54-3.48(m, 4H), 3.34-3.28 (m, 4H), 2.50-2.38 (m, 5H), 2.28-2.14 (m, 2H).

Example 44[5-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₁H₂₈FN₃OS, 389.19; m/z found, 390.3 [M+H]⁺.¹H NMR (CDCl₃): 7.22 (d, J=8.9, 2H), 6.99 (d, J=2.8, 1H), 6.86-6.78 (m,4H), 4.67 (t, J=4.7, 1H), 4.57 (t, J=4.7, 1H), 3.68 (s, 2H), 3.24-3.18(m, 4H), 2.80 (t, J=4.8, 1H), 2.75-2.69 (m, 5H), 2.45 (s, 3H), 2.40 (s,3H), 2.01 (br s, 1H).

Example 45[5-(4-Cyclopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₂H₂₉N₃OS, 383.20; m/z found, 384.3 [M+H]⁺.¹H NMR (CDCl₃): 7.21 (d, J=8.8, 2H), 7.02 (d, J=2.5, 1H), 6.85 (d,J=8.8, 2H), 6.80-6.78 (m, 2H), 3.93 (s, 2H), 3.11-3.08 (m, 4H),2.75-2.72 (m, 4H), 2.49 (s, 3H), 2.44 (s, 3H), 1.67-1.62 (m, 1H),0.50-0.41 (m, 4H).

Example 46[5-(4-Cyclopropyl-piperazin-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₁H₂₅Cl₂N₃O, 405.14; m/z found, 406.7 [M+H]⁺.¹H NMR (CDCl₃): 7.36 (d, J=8.8, 1H), 7.08 (d, J=2.7, 1H), 7.01 (d,J=2.8, 1H), 6.88-6.80 (m, 3H), 4.00 (s, 2H), 3.18-3.11 (m, 4H),2.82-2.77 (m, 4H), 2.55 (s, 3H), 1.76-1.68 (m, 1H), 0.55-0.51 (m, 4H).

Example 47[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazin-1-yl)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₁H₂₇Cl₂N₃O, 407.15; m/z found, 408.2 [M+H]⁺.¹H NMR (CDCl₃): 7.32 (d, J=8.9, 1H), 7.01 (d, J=2.7, 1H), 6.96 (d,J=2.8, 1H), 6.87-6.80 (m, 2H), 6.75 (dd, J=8.9, 2.8, 1H), 3.68 (s, 2H),3.24-3.20 (m, 4H), 2.80-2.73 (m, 1H), 2.73-2.70 (m, 4H), 2.42 (s, 3H),1.11 (d, J=6.5, 6H).

Example 481-[3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one

MS (ESI): mass calcd. for C₁₉H₂₃N₃O₂S, 357.15; m/z found, 358.4 [M+H]⁺.¹H NMR (CDCl₃): 7.42-7.38 (m, 1H), 7.28-7.24 (m, 2H), 7.134 (dd, J=8.6,2.6, 1H), 6.96-6.92 (m, 2H), 6.85-6.82 (m, 1H), 3.91-3.79 (m, 2H),3.72-3.64 (m, 4H), 3.24-3.18 (m, 2H), 2.47 (s, 6H).

Example 494-Isopropyl-1-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one

MS (ESI): mass calcd. for C₂₂H₂₉N₃O₂S, 399.20; m/z found, 400.2 [M+H]⁺.¹H NMR (CDCl₃): 7.36 (d, J=2.6, 1H), 7.24 (d, J=8.8, 2H), 7.13 (dd,J=8.6, 2.6, 1H), 6.92 (d, J=8.8, 2H), 6.81 (d, J=8.7, 1H), 3.84 (s, 2H),3.67-3.63 (m, 2H), 3.63-3.58 (m, 1H), 3.36 (s, 2H), 2.84-2.80 (m, 2H),2.80-2.73 (m, 1H), 2.46 (s, 6H), 1.09 (d, J=6.5, 6H).

Example 501-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-4-isopropyl-piperazin-2-one

MS (ESI): mass calcd. for C₂₁H₂₅Cl₂N₃O₂, 421.13; m/z found, 422.3[M+H]⁺. ¹H NMR (CDCl₃): 7.41 (d, J=2.6, 1H), 7.37 (d, J=8.8, 1H), 7.20(dd, J=8.6, 2.6, 1H), 7.09 (d, J=2.8, 1H), 6.90 (d, J=8.6, 1H), 6.84(dd, J=8.8, 2.8, 1H), 3.75 (s, 2H), 3.71-3.68 (m, 2H), 3.40 (s, 2H),2.87-2.84 (m, 2H), 2.82-2.75 (m, 1H), 2.45 (s, 3H), 1.11 (d, J=6.5, 6H).

Example 51Methyl-[2-(4-methylsulfanyl-phenoxy)-5-(4-morpholin-4-yl-piperidin-1-yl)-benzyl]-amine

MS (ESI): mass calcd. for C₂₄H₃₃N₃O₂S, 427.23; m/z found, 428.4 [M+H]⁺.¹H NMR (CDCl₃): 7.23 (d, J=8.8, 2H), 7.02 (d, J=2.3, 1H), 6.84 (d,J=8.8, 2H), 6.83-6.81 (m, 2H), 3.80 (s, 2H), 3.76-3.72 (m, 4H),3.70-3.65 (m, 2H), 2.70 (td, J=12.1, 2.1, 2H), 2.60-2.56 (m, 4H), 2.46(s, 6H), 2.33-2.26 (m, 1H), 1.97-1.91 (m, 2H), 1.69-1.58 (m, 2H).

Example 52[5-(4-Isopropyl-[1,4]diazepan-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₃H₃₃N₃OS, 399.23; m/z found, 400.4 [M+H]⁺.¹H NMR (MeOD): 7.37 (s, 1H), 7.32 (d, J=8.6, 2H), 7.17-7.12 (m, 1H),7.00 (d, J=8.7, 2H), 6.92 (d, J=9.0, 1H), 4.25 (s, 2H), 4.02-3.96 (m,2H), 3.78-3.65 (m, 4H), 3.64-3.52 (m, 2H), 3.36-3.32 (m, 1H), 2.77 (s,3H), 2.47 (s, 3H), 2.46-2.38 (m, 2H), 1.43 (d, J=6.5, 6H).

Example 53[5-(4-Cyclopropyl-[1,4]diazepan-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₃H₃₁N₃Os, 397.22; m/z found, 398.3 [M+H]⁺.¹H NMR (CDCl₃): 7.23 (d, J=8.8, 2H), 6.90 (d, J=2.9, 1H), 6.85 (d,J=8.8, 2H), 6.82 (d, J=9.0, 1H), 6.62 (dd, J=9.0, 3.0, 1H), 4.06 (s,2H), 3.65-3.60 (m, 2H), 3.42 (t, J=6.2, 2H), 3.36-3.27 (m, 2H),3.23-3.14 (m, 2H), 2.62 (s, 3H), 2.46 (s, 3H), 2.30-2.23 (m, 1H),2.22-2.14 (m, 2H), 1.03-0.93 (m, 2H), 0.74-0.68 (m, 2H).

Example 541-Isopropyl-4-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-[1,4]diazepan-5-one

MS (ESI): mass calcd. for C₂₃H₃₁N₃O₂S, 413.21; m/z found, 414.4 [M+H]⁺.¹H NMR (CDCl₃): 7.35-7.30 (m, 1H), 7.28-7.24 (m, 2H), 7.08-7.03 (m, 1H),7.00-6.96 (m, 1H), 6.94-6.91 (m, 1H), 6.85 (t, J=8.2, 1H), 3.84-3.80 (m,2H), 3.78 (d, J=4.0, 2H), 2.99-2.91 (m, 1H), 2.85-2.76 (m, 6H), 2.45 (s,3H), 2.00-1.90 (m, 3H), 1.06 (d, J=6.6, 6H).

Example 55[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-[1,4]diazepan-1-yl)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₂H₂₉Cl₂N₃O, 421.17; m/z found, 422.2 [M+H]⁺.¹H NMR (CDCl₃): 7.30 (d, J=8.9, 1H), 6.95 (d, J=2.8, 1H), 6.82 (d,J=8.9, 1H), 6.74 (dd, J=8.9, 2.9, 1H), 6.73-6.71 (m, 1H), 6.58 (dd,J=8.9, 3.1, 1H), 3.62 (s, 2H), 3.58-3.54 (m, 2H), 3.52 (t, J=6.2, 2H),3.03-2.95 (m, 1H), 2.83-2.80 (m, 2H), 2.66-2.62 (m, 2H), 2.41 (s, 3H),2.00-1.94 (m, 2H), 1.04 (d, J=6.6, 6H).

Example 56[5-(4-Cyclopropyl-[1,4]diazepan-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₂H₂₇Cl₂N₃O, 419.15; m/z found, 420.8 [M+H]⁺.¹H NMR (CDCl₃): 7.30 (d, J=8.9, 1H), 6.95 (d, J=2.8, 1H), 6.83 (d,J=8.9, 1H), 6.74 (dd, J=8.9, 2.8, 1H), 6.72 (d, J=3.1, 1H), 6.78 (dd,J=8.9, 1H), 3.61 (s, 2H), 3.54-3.47 (m, 4H), 2.96-2.92 (m, 2H),2.82-2.78 (m, 2H), 241 (s, 3H), 1.98-1.92 (m, 2H), 1.87-1.82 (m, 2H),0.49-0.44 (m, 2H), 0.43-0.38 (m, 2H).

Example 571-Cyclopropyl-4-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-[1,4]diazepan-5-one

MS (ESI): mass calcd. for C₂₃H₂₉N₃O₂S, 411.20; m/z found, 412.8 [M+H]⁺.¹H NMR (CDCl₃): 7.27-7.24 (m, 3H), 7.05 (dd, J=8.6, 2.6, 1H), 6.92 (d,J=8.8, 2H), 6.83 (d, J=8.6, 1H), 3.79-3.75 (m, 4H), 2.94-2.90 (m, 4H),2.81-2.77 (m, 2H), 2.48 (s, 3H), 2.46 (s, 3H), 1.80-1.76 (m, 1H),0.56-0.51 (m, 2H), 0.47-0.43 (m, 2H).

Example 58(S)-Dimethyl-{1-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-pyrrolidin-3-yl}-amine

MS (ESI): mass calcd. for C₂₁H₂₉N₃OS, 371.20; m/z found, 372.7 [M+H]⁺.¹H NMR (CDCl₃): 7.21 (d, J=8.9, 2H), 6.86 (d, J=8.7, 1H), 6.81 (d,J=8.8, 2H), 6.57 (d, J=2.9, 1H), 6.43 (dd, J=8.8, 3.0, 1H), 3.66 (s,2H), 3.53-3.48 (m, 1H), 3.45 (td, J=9.0, 2.1, 1H), 3.37-3.30 (m, 1H),3.17 (t, J=8.4, 1H), 2.88-2.80 (m, 1H), 2.45 (s, 3H), 2.40 (s, 3H), 2.32(s, 6H), 2.25-2.19 (m, 1H), 1.97-1.88 (m, 1H).

Example 59(4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-benzyloxy)-3-methylaminomethyl-phenyl]-methanone

Step A: [5-Bromo-2-(3,4-dichloro-benzyloxy)-benzyl]-methyl-carbamic acidtert-butyl ester. A mixture of(5-bromo-2-hydroxy-benzyl)-methyl-carbamic acid tert-butyl ester (1.0 g,3.2 mmol), K₂CO₃ (655 mg, 4.74 mmol), and4-bromomethyl-1,2-dichloro-benzene (1.14 g, 4.74 mmol) in CH₃CN (6.3 mL)was heated at 90° C. overnight. The mixture was then cooled to rt,diluted with EtOAc and water, and extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried (Na₂SO₄), andconcentrated. Purification by FCC (EtOAc/hexanes) gave the desiredproduct (1.49 g, 99%). ¹H NMR (CDCl₃, mixture of rotamers): 7.49 (d,J=1.9, 1H), 7.46 (d, J=7.8, 1H), 7.31 (dd, J=8.7, 2.0, 1H), 7.28-7.22(m, 2H), 6.73 (d, J=8.6, 1H), 5.00 (s, 2H), 4.52-4.38 (m, 2H), 2.90-2.80(m, 3H), 1.52-1.39 (m, 9H).

Step B. The title compound was prepared in an analogous fashion toExample 1, Steps D-E. MS (ESI): mass calcd. for C₂₃H₂₇Cl₂N₃O₂, 447.15;m/z found, 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.51 (d, J=1.8, 1H), 7.45 (d,J=8.2, 1H), 7.36 (d, J=2.0, 1H), 7.29 (dd, J=8.3, 2.1, 1H), 7.24 (dd,J=8.3, 1.9, 1H), 6.85 (d, J=8.4, 1H), 5.06 (s, 2H), 3.81 (s, 2H),3.75-3.32 (m, 4H), 2.72-2.48 (m, 4H), 2.44 (s, 3H), 2.21 (br s, 1H),1.64-1.58 (m, 1H), 0.47-0.43 (m, 2H), 0.42-0.39 (m, 2H).

Example 60Cyclopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine

Step A: 2-(5-Bromo-2-fluoro-phenyl)-[1,3]dioxolane. A mixture of5-bromo-2-fluoro-benzaldehyde (24.92 g, 123.2 mmol), ethylene glycol(21.0 mL, 369.6 mmol), toluene (650 mL), and TsOH (2.49 g, 12.4 mmol)were heated at reflux under a N₂ atmosphere in a flask fitted with aDean Stark trap and condenser. After 18 h, the mixture was cooled to rt,washed with a satd. aq. NaHCO₃ and brine, dried (MgSO₄), andconcentrated. Purification by FCC (EtOAc/hexanes) gave the desiredproduct (28.74 g, 95%) as an oil. ¹H NMR (CDCl₃): 7.68-7.63 (m, 1H),7.45-7.39 (m, 1H), 6.98-6.91 (m, 1H), 6.05-6.00 (m, 1H), 4.12 (brs, 2H),4.02 (brs, 2H).

Step B: 3-[1,3-Dioxolan-2-yl-4-fluoro-benzaldehyde. To a −78° C.solution of 2-(5-bromo-2-fluoro-phenyl)-[1,3]dioxolane (1.024 g, 4.047mmol) in THF (40 mL) was added 2.5 M n-BuLi (1.80 mL, 4.45 mmol). After20 min, the reaction was quenched with DMF (1.60 mL). After stirring for1 h, the mixture was diluted with DCM, washed with a satd. aq. NaHCO₃,dried (MgSO₄), and concentrated. Purification by FCC (EtOAc/hexanes)gave the desired product (406.5 mg, 87%) as a white solid. ¹H NMR(acetone-d₆): 10.05 (s, 1H), 8.17-8.09 (m, 1H), 8.06-7.97 (m, 1H),7.43-7.33 (m, 1H), 6.10-6.04 (m, 1H), 4.19-4.11 (m, 2H), 4.08-4.00 (m,2H).

Step C: 1-(3-[1,3]Dioxolan-2-yl-4-fluoro-benzyl)-4-isopropyl-piperazine

The title compound was prepared in an analogous fashion to Example 1,Step B, using NaBH(OAc)₃ instead of NaBH₄ (770.8 mg, 85%). MS (ESI):mass calcd. for C₁₇H₂₅FN₂O₂, 308.19; m/z found, 309.4 [M+H]⁺. ¹H NMR(CDCl₃): 7.45 (dd, J=6.9, 1H), 7.34-7.30 (m, 1H), 7.03-6.98 (m, 1H),6.06 (s, 1H), 4.18-4.15 (m, 2H), 4.06-4.03 (m, 2H), 3.47 (s, 2H),2.68-2.38 (m, 9H), 1.04 (d, J=6.5, 6H).

Step D: 2-Fluoro-5-(4-isopropyl-piperazin-1-ylmethyl)-benzaldehyde. Amixture of 1-(3-[1,3]dioxolan-2-yl-4-fluoro-benzyl)-4-isopropyl-piperazine (695.2 mg, 2.25mmol) and 6 N HCl (25 mL) was stirred at rt for 50 min, then was dilutedwith DCM (250 mL), and quenched slowly with 1 N NaOH. The organic layerwas separated, dried (Na₂SO₄), and concentrated to give the desiredproduct (573.5 mg, 96%). MS (ESI): mass calcd. for C₁₅H₂₁FN₂O, 264.16;m/z found, 265.3 [M+H]⁺. ¹H NMR (MeOD): 10.29 (s, 1H), 7.82-7.81 (m,1H), 7.68-7.66 (m, 1H), 7.58-7.56 (m, 1H), 7.31-7.28 (m, 1H), 7.26-7.04(m, 1H), 7.03-7.01 (t, J=8.4, 1H), 3.55 (s, 1H), 3.50 (s, 1H), 2.64-2.40(br m, 9H), 1.07-1.06 (m, 6H).

Step E:5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzaldehyde.A mixture of 2-fluoro-5-(4-isopropyl-piperazin-1-ylmethyl)-benzaldehyde(513.7 mg, 1.943 mmol), 4-methylsulfanyl-phenol (326.8 mg, 2.138 mmol),and K₂CO₃ (845.2 mg, 5.829 mmol) in DMF (9.0 mL) was heated at 90° C.for 3 days. After cooling to rt, the mixture was diluted with Et₂O,washed with 1 N NaOH and brine, dried (Na₂SO₄), and concentrated.Purification by FCC followed by reverse phase chromatography gave thedesired product (804.5 mg, >100%). MS (ESI): mass calcd. forC₂₂H₂₈N₂O₂S, 384.19; m/z found, 385.3 [M+H]⁺.

Step F. The title compound was prepared in an analogous fashion toExample 1, Step B, using NaB(OAc)₃H, to give the desired product. MS(ESI): mass calcd. for C₂₅H₃₅N₃OS, 425.25; m/z found, 426.4 [M+H]⁺. ¹HNMR (MeOD): 7.42-7.40 (m, 1H), 7.29 (d, J=8.8, 2H), 7.23 (dd, J=8.3,2.1, 1H), 6.92 (d, J=8.8, 2H), 6.84 (d, J=8.3, 1H), 4.88 (s, 2H), 3.83(s, 2H), 3.53 (s, 2H), 2.68-2.49 (m, 8H), 2.46 (s, 3H), 2.15-2.09 (m,1H), 1.08 (d, J=6.5, 6H), 0.46-0.42 (m, 2H), 0.38-0.34 (m, 2H).

The compounds in Examples 61-65 were prepared by a sequence similar tothat described in Example 60.

Example 61[5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine

MS (ESI): mass calcd. for C₂₃H₃₃N₃OS, 399.23; m/z found, 400.40 [M+H]⁺.¹H NMR (MeOD): 7.40-7.38 (m, 1H), 7.30-7.28 (m, 2H), 7.24-7.22 (m, 1H),6.93-6.91 (m, 2H), 6.82 (d, J=8.0, 1H), 3.73 (s, 2H), 3.53 (s, 2H),2.66-2.50 (m, 9H), 2.45 (s, 3H), 2.36 (s, 3H), 1.08 (d, J=6.5, 6H).

Example 62[5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-dimethyl-amine

¹H NMR (MeOD): 7.41 (d, J=2.0, 1H), 7.29-7.26 (m, 2H), 7.26-7.24 (m,1H), 6.90-6.88 (m, 2H), 6.83 (d, J=8.5, 1H), 3.54 (s, 4H), 2.74-2.48 (brm, 9H), 2.45 (s, 3H), 2.27 (s, 6H), 1.08 (d, J=6.5, 6H).

Example 63Ethyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine

MS (ESI): mass calcd. for C₂₄H₃₅N₃OS, 413.25; m/z found, 414.4 [M+H]⁺.¹H NMR (MeOD): 7.42-7.39 (m, 1H), 7.30 (d, J=8.8, 2H), 7.24 (dd, J 8.3,2.1, 1H), 6.92 (d, J=8.8, 2H), 6.84 (d, J=8.3, 1H), 4.91 (s, 3H), 3.78(s, 2H), 3.54 (s, 2H), 2.68-2.48 (m, 9H), 2.46 (s, 3H), 1.12-1.06 (m,9H).

Example 64Isopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine

MS (ESI): mass calcd. for C₂₅H₃₇N₃OS, 427.27; m/z found, 428.4 [M+H]⁺.¹H NMR (MeOD): 7.44 (d, J=2.0, 1H), 7.29 (d, J=8.7, 2H), 7.23 (dd,J=8.3, 2.1, 1H), 6.91 (d, J=8.9, 2H), 6.84 (d, J=8.3, 1H), 4.90 (s, 3H),3.77 (s, 2H), 3.53 (s, 2H), 2.80-2.73 (m, 1H), 2.72-2.47 (m, 7H), 2.45(s, 3H), 1.08 (d, J=6.5, 6H), 1.05 (d, J=6.3, 6H).

Example 655-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzylamine

MS (ESI): mass calcd. for C₂₂H₃₁N₃OS, 385.22; m/z found, 386.4 [M+H]⁺.¹H NMR (MeOD): 7.43-7.39 (m, 1H), 7.27 (d, J=8.8, 2H), 7.20 (dd, J=8.3,2.0, 1H), 6.91 (d, J=8.8, 2H), 6.80 (d, J=8.2, 1H), 4.95-4.86 (m, 2H),3.80 (s, 2H), 3.52 (s, 2H), 2.74-2.47 (m, 7H), 2.45 (s, 3H), 1.08 (d,J=6.5, 6H).

Example 664-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-1-isopropyl-piperazin-2-one

Step A: [2-(3,4-Dichloro-phenoxy)-5-formyl-benzyl]-methyl-carbamic acidtert-butyl ester. The title compound was prepared from[5-bromo-2-(3,4-dichloro-phenoxy)benzyl]methyl carbamic acid tert-butylester (Example 1, Steps A-C) in analogous fashion to Example 60, Step B.

Step B:[2-(3,4-Dichloro-phenoxy)-5-(3-oxo-piperazin-1-ylmethyl)-benzyl]-methyl-carbamicacid tert-butyl ester. The title compound was prepared in analogousfashion to Example 60, Step C.

Step C:[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-3-oxo-piperazin-1-ylmethyl)-benzyl]-methyl-carbamicacid tert-butyl ester. To a solution of[2-(3,4-dichloro-phenoxy)-5-(3-oxo-piperazin-1-ylmethyl)-benzyl]-methyl-carbamicacid tert-butyl ester 79 mg, 0.16 mmol) in DMF (3.2 mL) at 0° C. wasadded NaH (90%, 7.6 mg). After 30 min, 2-bromopropane (15 μL, 0.16 mmol)was added and the reaction was allowed to come to rt and stir overnight.The mixture was quenched with satd. aq. NaHCO₃ and extracted with DCM.The combined organic layers were dried (Na₂SO₄) and concentrated. Thecrude product was purified by FCC to provide the title compound (35 mg,41%). MS (ESI): mass calcd. for C₂₇H₃₅Cl₂N₃O₄, 535.20; m/z found, 536.2[M+H].

Step D. The title compound was prepared in an analogous fashion toExample 1, Step E. MS (ESI): mass calcd. for C₂₂H₂₇Cl₂N₃O₂, 435.15; m/zfound, 436.1 [M+H]⁺.

Example 671-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-4-isopropyl-piperazin-2-one

Step A:[2-(3,4-Dichloro-phenoxy)-5-hydroxymethyl-benzyl]-methyl-carbamic acidtert-butyl ester. To a solution of[2-(3,4-dichloro-phenoxy)-5-formyl-benzyl]-methyl-carbamic acidtert-butyl ester (816 mg, 1.98 mmol) in MeOH (40 mL), was added NaBH₄(75 mg, 1.98 mmol). After 24 h, the mixture was treated with 1 N NaOH,was stirred an additional 1 h, and then partially concentrated. Theresulting aqueous mixture was extracted with DCM and the combinedorganic layers were dried (Na₂SO₄) and concentrated. The crude materialwas carried forward without further purification (784 mg, 96%). MS(ESI): mass calcd. for C₂₀H₂₃Cl₂NO₄, 411.10; m/z found, 434.7 [M+Na]⁺.

Step B: [5-Chloromethyl-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-carbamicacid tert-butyl ester. To a solution of2-(3,4-dichloro-phenoxy)-5-hydroxymethyl-benzyl]-methyl-carbamic acidtert-butyl ester (248 mg, 0.61 mmol) in DCM was added K₂CO₃ (250 mg,1.80 mmol). The mixture was cooled to 0° C. and SOCl₂ (85 μL, 1.2 mmol)was added. After 2 h, the solids were filtered off and the filtrate wasconcentrated. Purification by FCC gave the desired product (241 mg,93%). MS (ESI): mass calcd. for C₂₀H₂₂Cl₃NO₃, 429.07; m/z found,330.6[M+H-Boc]⁺.

Step C:[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-2-oxo-piperazin-1-ylmethyl)-benzyl]-methyl-carbamicacid tert-butyl ester. To a solution of 4-isopropyl-piperazin-2-one (32mg, 0.22 mmol) in DMF (2.2 mL) at 0° C. was added NaH (90%, 11 mg).After 30 min, a solution of[5-chloromethyl-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-carbamic acidtert-butyl ester (96 mg, 0.22 mmol) in DMF (2.2 mL) was added and thereaction was allowed to come to rt and stir overnight. The mixture wasquenched with satd. aq. NaHCO₃ and extracted with DCM. The combinedorganic layers were dried (Na₂SO₄) and concentrated. The crude productwas purified by FCC to provide the desired product (94 mg, 79%). MS(ESI): mass calcd. for C₂₇H₃₅Cl₂N₃O₄, 535.20; m/z found, 536.2 [M+H].

Step D. The title compound was prepared in an analogous fashion toExample 1, Step E. MS (ESI): mass calcd. for C₂₂H₂₇Cl₂N₃O₂, 435.15; m/zfound, 436.1 [M+H].

Example 681-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-4-isopropyl-[1,4]diazepan-5-one

MS (ESI): mass calcd. for C₂₃H₂₉Cl₂N₃O₂, 449.16; m/z found, 450.1[M+H]⁺.

Example 694-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-1-isopropyl-[1,4]diazepan-5-one

MS (ESI): mass calcd. for C₂₃H₂₉Cl₂N₃O₂, 449.16; m/z found, 450.2[M+H]⁺.

Example 701-Cyclobutyl-4-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-benzyl]-[1,4]diazepan-5-one

MS (ESI): mass calcd. for C₂₄H₂₉Cl₂N₃O₂, 461.16; m/z found, 462.1[M+H]⁺.

The compounds in Examples 71-88 were prepared using methods analogous tothose described in the preceding examples.

Example 714-(3-Chloro-phenoxy)-3-methylaminomethyl-N-(2-pyrrolidin-1-yl-ethyl)-benzamide

MS (ESI): m/z found, 388.7 [M+H]⁺.

Example 72[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone

MS (ESI): m/z found, 414.8 [M+H]⁺.

Example 734-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-1-isopropyl-[1,4]diazepan-5-one

MS (ESI): m/z found, 436.8 [M+H]⁺.

Example 74(4-Cyclobutyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone

MS (ESI): m/z found, 448.2 [M+H]⁺.

Example 75(4-Cyclopentyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone

MS (ESI): m/z found, 462.3 [M+H]⁺.

Example 76[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone

MS (ESI): m/z found, 428.4 [M+H]⁺.

Example 77[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone

MS (ESI): m/z found, 414.3 [M+H]⁺.

Example 78[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone

MS (ESI): m/z found, 428.4 [M+H]⁺.

Example 79(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-pyridin-2-ylsulfanyl)-phenyl]-methanone

Example 80(4-Cyclopropyl-piperazin-1-yl)-[4-dimethylaminomethyl-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-methanone

MS (ESI): m/z found, 409.3 [M+H]⁺.

Example 81(3-Benzyloxy-4-dimethylaminomethyl-phenyl)-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): m/z found, 394.3 [M+H]⁺.

Example 82[4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone

MS (ESI): m/z found, 497.3 [M+H]⁺.

Example 83[3-(2,6-Dimethyl-pyridin-3-yloxy)-4-morpholin-4-ylmethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): m/z found, 453.3 [M+H]⁺.

Example 84(4-Dimethylaminomethyl-3-phenoxy-phenyl)-piperidin-1-yl-methanone

MS (ESI): m/z found, 339.2 [M+H]⁺.

Example 85(4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-phenoxy-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone

MS (ESI): m/z found, 470.3 [M+H]⁺.

Example 86[4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-(pyridin-3-yloxy)-phenyl]-(4-dimethylamino-piperidin-1-yl)-methanone

MS (ESI): m/z found, 471.3 [M+H]⁺.

Example 87[4-(4-Isopropyl-piperazin-1-ylmethyl)-3-phenoxy-phenyl]-piperidin-1-yl-methanone

MS (ESI): m/z found, 422.3 [M+H]⁺.

Example 88[4-(4-Isopropyl-piperazin-1-ylmethyl)-3-(pyridin-3-yloxy)-phenyl]-piperidin-1-yl-methanone

MS (ESI): m/z found, 423.3 [M+H]⁺.

Example 894-Dimethylaminomethyl-N-(2-methylamino-ethyl)-3-(pyridin-3-yloxy)-benzamide

To a solution of{2-[4-dimethylaminomethyl-3-(pyridin-3-yloxy)-benzoylamino]-ethyl}-methyl-carbamicacid tert-butylester (250 mg, 0.58 mmol) in CH₂Cl₂ (3 mL) was addedtrifluoroacetic acid (1 mL). The reaction was allowed to stir at rt for16 h and then concentrated under reduced pressure. The residue wasdissolved in CH₂Cl₂ (50 mL), washed with 1 M NaOH (15 mL), dried(Na₂SO₄), and concentrated under reduced pressure. FCC purification(MeOH/CH₂Cl₂) provided the desired product (0.13 g, 68%) as a yellowoil. MS (ESI): m/z found, 329.2 [M+H]⁺.

Example 90N-[2-(Cyclopropyl-methyl-amino)-ethyl]-4-dimethylaminomethyl-3-(pyridin-3-yloxy)-benzamide

To a solution of4-dimethylaminomethyl-N-(2-methylamino-ethyl)-3-(pyridin-3-yloxy)-benzamide(0.090 g, 0.274 mmol) in a 1:1 mixture of THF:MeOH (4 mL) was added[(1-ethoxycyclopropyl)-oxy]trimethylsilane (0.28 mL, 1.37 mmol), AcOH(0.08 mL, 1.37 mmol), and NaCNBH₃ (0.088 g, 1.37 mmol). The reactionmixture was heated to 50° C. for 24 h, cooled to rt and concentratedunder reduced pressure. The residue was dissolved in CH₂Cl₂ (15 mL),washed with sat. NaHCO₃ (5 mL), dried (Na₂SO₄), and concentrated. HPLCpurification under basic conditions yielded the desired product (0.036g, 38%). MS (ESI): m/z found, 369.2 [M+H]⁺.

Example 91[5-(4-Isopropyl-piperazine-1-carbonyl)-2-(3-methoxy-phenoxy)-benzyl]-methyl-carbamicacid tert-butyl ester

The title compound was prepared using methods analogous to thosedescribed in the preceding examples.

Biological Methods:

Compounds were tested as the free base, hydrochloride salt, TFA salt, orcitric acid salt forms.

H₃ Receptor Binding

Binding of compounds to the cloned human and rat H₃ receptors, stablyexpressed in SK-N-MC cells, was performed as described by Barbier, A. J.et al. (Br. J. Pharmacol. 2004, 143(5), 649-661). Data for compoundstested in this assay are presented in Table 1.

Rat Brain SERT

A rat brain without cerebellum (Zivic Laboratories, Inc.—Pittsburgh,Pa.) was homogenized in a 52.6 mM Tris pH 8/126.4 mM NaCl/5.26 mM KClmixture and centrifuged at 1,000 rpm for 5 min. The supernatant wasremoved and re-centrifuged at 15,000 rpm for 30 min. Pellets werere-homogenized in a 52.6 mM Tris pH8/126.4 mM NaCl/5.26 mM KCl mixture.Membranes were incubated with 0.6 nM [³H]-Citalopram plus/minus testcompounds for 60 min at 25° C. and harvested by rapid filtration overGF/C glass fiber filters (pretreated with 0.3% polyethylenimine)followed by four washes with ice-cold buffer. Nonspecific binding wasdefined in the presence of 100 μM fluoxetine. IC₅₀ values weredetermined by a single site curve-fitting program (GraphPad, San Diego,Calif.) and converted to K_(i) values based on a [³H]-Citalopram K_(d)of 0.6 nM and a ligand concentration of 0.6 nM. Data for compoundstested in this assay are presented in Table 1. NT=not tested.

TABLE 1 Human H₃ Rat SERT Ex. K_(i) (nM) K_(i) (nM) 1 2.4 4.9 2 29 4.0 32.2 1.8 4 4.3 5.8 5 23 9.3 6 1.1 18 7 1.1 8.2 8 0.8 90 9 1 160 10 33 26011 14 113 12 8 230 13 15 102 14 37 16 15 22 2000 16 21 4.2 17 1.5 150018 11 9.7 19 14 40 20 59 190 21 32 19 22 18 21 23 50 3 24 31 130 25 70.9 26 100 3 27 48 0.8 28 150 NT 29 170 10000 30 3 4000 31 10 1000 32 266000 33 2 10000 34 3 10000 35 7 10000 36 4 28 37 1 2 38 4 130 39 15 1740 7 0.1 41 210 0.4 42 6 0.3 43 110 0.7 44 160 0.5 45 76 1 46 49 4 47 202 48 5500 0.4 49 400 2 50 150 7 51 28 2 52 8 1 53 28 6 54 3 0.5 55 27 1056 25 16 57 37 4 58 300 6 59 70 4 60 2 3 61 2 0.8 62 21 1 63 0.9 6 640.5 7 65 4 18 66 2500 6 67 6 4 68 6300 7 69 110 4 70 19 5 71 6 2 72 4 6573 7.7 12 74 4 9 75 20 11 76 2 28 77 2.4 10 78 3.4 8.1 79 28 3150 80 140500 81 67 8000 82 200 NT 83 21 NT 84 4500 NT 85 12 NT 86 200 NT 87 280NT 88 220 NT 89 1900 NT 90 45 NT 91 58 NT

Human SERT

Homogenized HEK293 (Human Embryonic Kidney) membranes expressing thehuman SERT were incubated with ³H-citalopram (SERT) at rt for 1 h in 50mM Tris, 120 mM NaCl, 5 mM KCl (pH 7.4). Nonspecific binding wasdetermined in the presence of 10 μM fluoxetine for the SERT. Themembranes were washed and the radioactivity was counted as above.Calculations for K_(i) at the SERT were based on a K_(d) value for³H-citalopram and a ligand concentration of 3.1 nM. Data for compoundstested in this assay are presented in Table 2.

TABLE 2 Human SERT Ex. K_(i) (nM) 1 6.3 2 5.0 3 5.9 4 8.1 5 6.8 6 28 724 9 420 11 155 12 380 13 363 14 37 16 11 17 2000 18 23 73 16 75 15 7739 78 24

Cyclic AMP Accumulation

Sublines of SK-N-MC cells were created that expressed a reporterconstruct and the human H₃ receptor. The reporter gene (β-galactosidase)is under the control of multiple cyclic AMP responsive elements. In96-well plates, histamine was added directly to the cell media followed5 min later by an addition of forskolin (5 μM final concentration). Whenappropriate, antagonists were added 10 min prior to agonist addition.After a 6-h incubation at 37° C., the media was aspirated and the cellswashed with 200 μL of phosphate-buffered saline followed by a secondaspiration. Cells were lysed with 25 μL 0.1× assay buffer (10 mMNa-phosphate, pH 8, 0.2 mM MgSO₄, 0.01 mM MnCl₂) and incubated at rt for10 min. Cells were then incubated for 10 min with 100 μL of 1× assaybuffer containing 0.5% Triton and 40 mM, mercaptoethanol. Color wasdeveloped using 25 μL of 1 mg/mL substrate solution (chlorophenolred β-Dgalactopyranoside; Roche Molecular Biochemicals, Indianapolis, Ind.).Color was quantitated on a microplate reader at absorbance 570 nM. ThepA₂ values were calculated by Schild regression analysis of the pEC₅₀values and are presented for compounds tested in Table 3.

TABLE 3 Ex. pA₂ 1 8.14 3 8.57 4 8.12 5 8.11 6 8.61 7 8.64 30 9.1 31 8.833 9.5 34 8.9 35 8.6 36 8.2 54 8.7 73 8.35

1. A compound of Formula (I):

wherein one of R^(1a) and R^(1b) is

 and the other is —H; R² and R³ are each independently selected from thegroup consisting of: —H; a —C₁₋₆alkyl group unsubstituted or substitutedwith —OH, —OC₁₋₄alkyl, —NH₂, —N(R^(a))R^(b), or —F; —CO₂C₁₋₄alkyl; and amonocyclic cycloalkyl group unsubstituted or substituted with—C₁₋₄alkyl, —OH, halo, or —CF₃; where R^(a) and R^(b) are eachindependently —H, —C₁₋₆alkyl, or monocyclic cycloalkyl, or R^(a) andR^(b) taken together with their nitrogen of attachment form a monocyclicheterocycloalkyl group; provided that R² and R³ are not both H; or,alternatively, R² and R³ taken together with the nitrogen to which theyare attached form a saturated monocyclic heterocycloalkyl groupunsubstituted or substituted on a carbon ring member with one, two, orthree R^(d) moieties and substituted on a nitrogen ring member with anR^(e) moiety; where each R^(d) moiety is independently selected from thegroup consisting of: —C₁₋₆alkyl; —C₁₋₄alkyl-OH; halo; —OH; —OC₁₋₆alkyl;ipso-substituted —OC₂₋₃alkylO—; —CN; —NO₂; —N(R^(g))R^(h);—C(O)N(R^(g))R^(h); —N(R^(g))SO₂C₁₋₆alkyl; —C(O)C₁₋₆alkyl;—S(O)₀₋₂—C₁₋₆alkyl; —SO₂N(R^(g))R^(h); —SCF₃; —CF₃; —OCF₃; —CO₂H; and—CO₂C₁₋₆alkyl; where R^(g) and R^(h) are each independently —H or—C₁₋₆alkyl, or R^(g) and R^(h) taken together with their nitrogen ofattachment form a monocyclic heterocycloalkyl group; and where R^(e) isselected from the group consisting of: —H; a —C₁₋₆alkyl or—C(O)C₁₋₆alkyl group unsubstituted or substituted with halo, —CN, —OH,—OC₁₋₄alkyl, or —CF₃; —C(O)CF₃; —S(O)₀₋₂—C₁₋₆alkyl; —CO₂C₁₋₆alkyl; and aphenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, ormonocyclic carbon-linked heterocycloalkyl group, each unsubstituted orsubstituted with —C₁₋₄alkyl, halo, —CN, —OH, —OC₁₋₄alkyl, or —CF₃; q is0 or 1; each R⁴ is independently —H or methyl, or both R⁴ substituentstaken together form a carbonyl; Y is —O—, —OCH₂—, —S—, —SO—, or —SO₂—;R⁵ is —H or —C₁₋₆alkyl; R⁶ is —H; or —C₁₋₆alkyl, —C₃₋₆alkenyl,—C₃₋₆alkynyl, monocyclic cycloalkyl, or —C₁₋₆alkyl-(monocycliccycloalkyl), each unsubstituted or substituted with —C₁₋₄alkyl, —OH,—OC₁₋₄alkyl, halo, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, —CO₂H, or—CO₂C₁₋₄alkyl; R⁷ is —H; or —C₁₋₆alkyl, —C₃₋₆alkenyl, —C₃₋₆alkynyl,monocyclic cycloalkyl, or —C₁₋₆alkyl-(monocyclic cycloalkyl), eachunsubstituted or substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, —CO₂H, or —CO₂C₁₋₄alkyl; orR⁶ and R⁷ taken together with their nitrogen of attachment form asaturated monocyclic heterocycloalkyl group unsubstituted or substitutedwith —C₁₋₄alkyl, —OC₁₋₄alkyl, or halo; and Cyc is a phenyl or monocycliccarbon-linked heteroaryl group, unsubstituted or substituted with one,two, or three R^(k) moieties; where each R^(k) moiety is independentlyselected from the group consisting of: —C₁₋₆alkyl, —CHF₂, —CF₃,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —OH, —OC₁₋₆alkyl, —OCHF₂, —OCF₃,—OC₃₋₆alkenyl, —OC₃₋₆alkynyl, —CN, —NO₂, —N(R^(l))R^(m),—N(R^(l))C(O)R^(m), —N(R^(l))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —C(O)N(R¹)R^(m), —SO₂N(R¹)R^(m), —SCF₃, halo, —CO₂H,and —CO₂C₁₋₆alkyl; or two R^(k) moieties on adjacent carbon atoms ofattachment together are —OC₁₋₄alkyleneO— to form a cyclic ring which isunsubstituted or substituted with one or two fluoro substituents; whereR^(l) and R^(m) are each independently —H or —C₁₋₆alkyl; provided thatwhen both R⁴ substituents taken together form a carbonyl, then R² and R³taken together are not diazepanyl; or a pharmaceutically acceptablesalt, a pharmaceutically acceptable prodrug, or a pharmaceuticallyactive metabolite thereof.
 2. A compound as defined in claim 1, whereinR^(1b) is


3. A compound as defined in claim 1, wherein R² and R³ are eachindependently —H; or methyl, ethyl, propyl, isopropyl, sec-butyl,2-methylpropyl, cyclopropyl, cyclobutyl, or cyclopentyl, eachunsubstituted or substituted as previously described.
 4. A compound asdefined in claim 1, wherein R² and R³ are each independently —H, methyl,ethyl, propyl, isopropyl, sec-butyl, 2-hydroxyethyl, 2-methoxyethyl,2-methylaminoethyl, 2-dimethylaminoethyl,2-(cyclopropyl-methyl-amino)-ethyl, 2-pyrrolidin-1-yl-ethyl,2-hydroxy-2-methylpropyl, 3-dimethylaminopropyl, cyclopropyl,cyclobutyl, or cyclopentyl.
 5. A compound as defined in claim 1, whereinR² and R³ are each independently —H, methyl, cyclopropyl,dimethylaminoethyl, or dimethylaminopropyl.
 6. A compound as defined inclaim 1, wherein R^(a) and R^(b) are each independently —H, methyl, orcyclopropyl, or R^(a) and R^(b) taken together form pyrrolidinyl.
 7. Acompound as defined in claim 1, wherein R² and R³ taken together withthe nitrogen to which they are attached form azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, homopiperidinyl, diazepanyl,piperazinonyl, or diazepanonyl, each unsubstituted or substituted aspreviously described.
 8. A compound as defined in claim 1, wherein R²and R³ taken together with the nitrogen to which they are attached formazetidinyl, 3,3-difluoroazetidinyl, pyrrolidinyl, 2-methylpyrrolidinyl,3-hydroxypyrrolidinyl, 3-dimethylaminopyrrolidinyl,2,5-dimethylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl,2-hydroxymethylpyrrolidinyl, 3,3-difluoropyrrolidinyl, piperidinyl,3-fluoropiperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl,4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl,4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro[4,5]dec-8-yl,4-cyanopiperidinyl, 4-carboethoxypiperidinyl, 3-hydroxypiperidinyl,4-hydroxypiperidinyl, 2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl, 4-hydroxymethylpiperidinyl, 3-hydroxyethylpiperidinyl,4-hydroxyethylpiperidinyl, 4-dimethylaminopiperidinyl,4-morpholin-4-yl-piperidin-1-yl, morpholinyl, 2-methylmorpholin-4-yl,3-methylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl,3-hydroxymethylmorpholin-4-yl, 2-hydroxymethylmorpholin-4-yl,piperazinyl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1-yl,4-(2-fluoroethyl)-piperazin-1-yl, 4-isopropyl-piperazin-1-yl,4-cyclopropyl-piperazin-1-yl, 4-cyclobutyl-piperazin-1-yl,4-cyclopentyl-piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,4-(2-methoxyethyl)-piperazin-1-yl,4-(tert-butoxycarbonyl)piperazin-1-yl, 4-phenylpiperazin-1-yl,4-(2-hydroxyphenyl)piperazinyl,4-(4-trifluoromethyl-phenyl)-piperazin-1-yl,4-thiazol-2-yl-piperazin-1-yl, 4-(2-thiophenyl)piperazinyl,4-pyridin-4-yl-piperazin-1-yl, 4-acetylpiperazin-1-yl,4-isobutyryl-piperazin-1-yl, 4-piperazin-2-onyl,1-isopropyl-4-piperazin-2-onyl, 4-isopropyl-1-piperazin-2-onyl,1-cyclopropyl-4-piperazin-2-onyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, 4-isopropyl-[1,4]diazepan-1-yl,4-cyclopropyl-[1,4]diazepan-1-yl, 1-cyclobutyl-4-diazepan-5-onyl,4-isopropyl-1-diazepan-5-onyl, 1-isopropyl-4-diazepan-5-onyl, or1-cyclopropyl-4-diazepan-5-onyl.
 9. A compound as defined in claim 1,wherein R² and R³ taken together with the nitrogen to which they areattached form pyrrolidinyl, 3-dimethylaminopyrrolidinyl, piperidinyl,4-fluoropiperidinyl, 4-dimethylaminopiperidinyl,4-morpholin-4-yl-piperidin-1-yl, morpholinyl, thiomorpholinyl,piperazinyl, 4-methyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl,4-(2-fluoroethyl)-piperazin-1-yl, 4-cyclopropyl-piperazin-1-yl,4-cyclobutyl-piperazin-1-yl, 4-cyclopentyl-piperazin-1-yl,4-pyridin-4-yl-piperazin-1-yl, 4-piperazin-2-onyl,1-isopropyl-4-piperazin-2-onyl, 4-isopropyl-[1,4]diazepan-1-yl, or1-isopropyl-4-diazepan-5-onyl.
 10. A compound as defined in claim 1,wherein each R^(d) moiety is independently selected from the groupconsisting of: methyl, ethyl, isopropyl, hydroxyethyl, fluoro, methoxy,dimethylamino, piperidinyl, morpholinyl, acetyl, trifluoromethyl, —CO₂H,and —CO₂-methyl.
 11. A compound as defined in claim 1, wherein R^(g) andR^(h) are each independently —H, methyl, ethyl, or isopropyl, or R^(g)and R^(h) taken together with their nitrogen of attachment formpyrrolidinyl, piperidinyl, morpolinyl, or thiomorpholinyl.
 12. Acompound as defined in claim 1, wherein R^(e) is selected from the groupconsisting of: —H, methyl, ethyl, isopropyl, 2-fluoroethyl,hydroxyethyl, methoxypropyl, acetyl, tert-butoxycarbonyl, phenyl,4-pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, and piperidinyl.
 13. Acompound as defined in claim 1, wherein R^(e) is selected from the groupconsisting of: —H, isopropyl, and cyclopropyl.
 14. A compound as definedin claim 1, wherein q is 1 and both R⁴ substituents taken together forma carbonyl.
 15. A compound as defined in claim 1, wherein q is
 0. 16. Acompound as defined in claim 1, wherein q is 1 and each R⁴ is —H.
 17. Acompound as defined in claim 1, wherein Y is —O— or —S—.
 18. A compoundas defined in claim 1, wherein Cyc is a phenyl or pyridyl groupunsubstituted or substituted with one, two, or three R^(k) moieties. 19.A compound as defined in claim 1, wherein Cyc is a thiophenyl, oxazolyl,thiazolyl, pyrazolyl, pyridinyl, or pyrazinyl group unsubstituted orsubstituted with one, two, or three R^(k) moieties.
 20. A compound asdefined in claim 1, wherein Cyc is phenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl,3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,4-ethylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,3-iodophenyl, 4-iodophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2-fluoro-3-chlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl,3-chloro-4-fluorophenyl, 4-fluoro-3-methylphenyl,3-chloro-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl,3-fluoro-4-methoxyphenyl, 3-chloro-4-difluoromethoxyphenyl,4-chloro-3-trifluoromethylphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,4-difluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,3-acetylphenyl, 4-acetylphenyl, 3-nitrophenyl, 4-nitrophenyl,4-aminophenyl, 4-dimethylaminophenyl, 4-carbamoylphenyl,4-methanesulfanylphenyl, 4-methanesulfinylphenyl,4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl,3-methyl-4-methylsulfanylphenyl, benzo[1,3]dioxol-4-yl,benzo[1,3]dioxol-5-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl,thiazol-5-yl, thiazol-2-yl, 2H-pyrazol-3-yl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 4-trifluoromethyl-pyridin-2-yl, 2,6-dimethyl-pyridin-3-yl,6-methyl-pyridin-3-yl, 2-chloro-5-pyridinyl,2-dimethylamino-5-pyridinyl, 6-methoxy-pyridin-3-yl,6-methylsulfanyl-pyridin-3-yl, 2-hydroxy-5-pyridinyl,6-bromo-pyridin-3-yl, or pyrazin-2-yl.
 21. A compound as defined inclaim 1, wherein Cyc is phenyl, 3-methoxyphenyl, 3-fluorophenyl,4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,3-chloro-2-fluorophenyl, 4-chloro-2-fluorophenyl,3-chloro-4-fluorophenyl, 4-trifluoromethylphenyl,4-methanesulfanylphenyl, 3-methyl-4-methanesulfanylphenyl, 2-pyridinyl,3-pyridinyl, or 6-methyl-3-pyridinyl.
 22. A compound as defined in claim1, wherein each R^(k) moiety is independently selected from the groupconsisting of: methyl, methoxy, fluoro, chloro, trifluoromethyl,methanesulfanyl, trifluoromethanesulfanyl, cyano, and trifluoromethoxy.23. A compound as defined in claim 1, wherein R^(l) and R^(m) are eachindependently —H or methyl.
 24. A compound as defined in claim 1,wherein R⁵ is —H or methyl.
 25. A compound as defined in claim 1,wherein R⁵ is —H.
 26. A compound as defined in claim 1, wherein R⁶ is—H, methyl, ethyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, orcyclopentyl, each unsubstituted or substituted as previously described.27. A compound as defined in claim 1, wherein R⁶ is —H or methyl.
 28. Acompound as defined in claim 1, wherein R⁷ is —H, methyl, ethyl, propyl,isopropyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, eachunsubstituted or substituted as previously described.
 29. A compound asdefined in claim 1, wherein R⁷ is methyl, ethyl, isopropyl, sec-butyl,cyclopropyl, cyclobutyl, or cyclopentyl.
 30. A compound as defined inclaim 1, wherein R⁷ is methyl, ethyl, isopropyl, or cyclopropyl.
 31. Acompound as defined in claim 1, wherein R⁶ and R⁷ taken together withtheir nitrogen of attachment form azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, homopiperidinyl, diazepanyl, orhomomorpholinyl, each unsubstituted or substituted as previouslydescribed.
 32. A compound as defined in claim 1, wherein R⁶ and R⁷ takentogether with their nitrogen of attachment form piperidinyl,pyrrolidinyl, morpholinyl, 4-isopropyl-piperazin-1-yl, orhomomorpholinyl.
 33. A compound selected from the group consisting of:[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone;(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone;(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone;(4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;(4-Isopropyl-piperazin-1-yl)-[4-(3-methoxy-phenoxy)-3-methylaminomethyl-phenyl]-methanone;[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;[4-(4-Chloro-phenoxy)-3-cyclopropylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone;(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone;[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;(4-Cyclopropyl-piperazin-1-yl)-(3-methylaminomethyl-4-phenoxy-phenyl)-methanone;(4-Cyclopropyl-piperazin-1-yl)-[4-(3-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-phenoxy)-phenyl]-methanone;[3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone;[3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;(4-Cyclopropyl-piperazin-1-yl)-[4-(4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-methanone;[4-(3-Chloro-4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;[4-(4-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;[3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone;[4-(3-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;(S)-3-Dimethylamino-pyrrolidin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone;4-(3-Chloro-phenoxy)-N-(2-dimethylamino-ethyl)-3-methylaminomethyl-benzamide;4-(3-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-methylaminomethyl-benzamide;[4-(4-Chloro-phenylsulfanyl)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-2-ylsulfanyl)-phenyl]-methanone;[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(3-dimethylamino-pyrrolidin-1-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone;(4-Cyclopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone;(3-Dimethylamino-pyrrolidin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone;[3-(4-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;[3-(3,4-Dichloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;[3-(3-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;(4-Cyclopropyl-piperazin-1-yl)-[3-(3,4-dichloro-phenoxy)-4-methylaminomethyl-phenyl]-methanone[5-(4-Isopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;Methyl-[5-(4-methyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine;[5-(4-Cyclobutyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;Methyl-[2-(4-methylsulfanyl-phenoxy)-5-(4-pyridin-4-yl-piperazin-1-yl)-benzyl]-amine;[5-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;[5-(4-Cyclopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine[5-(4-Cyclopropyl-piperazin-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine;[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazin-1-yl)-benzyl]-methyl-amine;1-[3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one;4-Isopropyl-1-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one;1-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-4-isopropyl-piperazin-2-one;Methyl-[2-(4-methylsulfanyl-phenoxy)-5-(4-morpholin-4-yl-piperidin-1-yl)-benzyl]-amine;[5-(4-Isopropyl-[1,4]diazepan-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;[5-(4-Cyclopropyl-[1,4]diazepan-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;1-Isopropyl-4-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-[1,4]diazepan-5-one;[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-[1,4]diazepan-1-yl)-benzyl]-methyl-amine;[5-(4-Cyclopropyl-[1,4]diazepan-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine;1-Cyclopropyl-4-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-[1,4]diazepan-5-one;(S)-Dimethyl-{1-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-pyrrolidin-3-yl}-amine;(4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-benzyloxy)-3-methylaminomethyl-phenyl]-methanone;Cyclopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine;[5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;[5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-dimethyl-amine;Ethyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine;Isopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine;5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzylamine;4-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-1-isopropyl-piperazin-2-one;1-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-4-isopropyl-piperazin-2-one;1-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-4-isopropyl-[1,4]diazepan-5-one;4-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-1-isopropyl-[1,4]diazepan-5-one;1-Cyclobutyl-4-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-benzyl]-[1,4]diazepan-5-one;4-(3-Chloro-phenoxy)-3-methylaminomethyl-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone;4-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-1-isopropyl-[1,4]diazepan-5-one;(4-Cyclobutyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;(4-Cyclopentyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone;[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone;[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone;(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-pyridin-2-ylsulfanyl)-phenyl]-methanone;(4-Cyclopropyl-piperazin-1-yl)-[4-dimethylaminomethyl-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-methanone;(3-Benzyloxy-4-dimethylaminomethyl-phenyl)-(4-cyclopropyl-piperazin-1-yl)-methanone;[4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;[3-(2,6-Dimethyl-pyridin-3-yloxy)-4-morpholin-4-ylmethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;(4-Dimethylaminomethyl-3-phenoxy-phenyl)-piperidin-1-yl-methanone;(4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-phenoxy-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;[4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-(pyridin-3-yloxy)-phenyl]-(4-dimethylamino-piperidin-1-yl)-methanone;[4-(4-Isopropyl-piperazin-1-ylmethyl)-3-phenoxy-phenyl]-piperidin-1-yl-methanone;[4-(4-Isopropyl-piperazin-1-ylmethyl)-3-(pyridin-3-yloxy)-phenyl]-piperidin-1-yl-methanone;4-Dimethylaminomethyl-N-(2-methylamino-ethyl)-3-(pyridin-3-yloxy)-benzamide;N-[2-(Cyclopropyl-methyl-amino)-ethyl]-4-dimethylaminomethyl-3-(pyridin-3-yloxy)-benzamide;and[5-(4-Isopropyl-piperazine-1-carbonyl)-2-(3-methoxy-phenoxy)-benzyl]-methyl-carbamicacid tert-butyl ester; and pharmaceutically acceptable salts thereof.34. A compound or pharmaceutically acceptable salt according to claim 1.35. A pharmaceutical composition for treating a disease, disorder, ormedical condition mediated by histamine H₃ receptor and/or serotonintransporter activity, comprising: (a) an effective amount of a compoundof Formula (I):

wherein one of R^(1a) and R^(1b) is

 and the other is —H; R² and R³ are each independently selected from thegroup consisting of: —H; a —C₁₋₆alkyl group unsubstituted or substitutedwith —OH, —OC₁₋₄alkyl, —NH₂, —N(R^(a))R^(b), or —F; —CO₂C₁₋₄alkyl; and amonocyclic cycloalkyl group unsubstituted or substituted with—C₁₋₄alkyl, —OH, halo, or —CF₃; where R^(a) and R^(b) are eachindependently —H, —C₁₋₆alkyl, or monocyclic cycloalkyl, or R^(a) andR^(b) taken together with their nitrogen of attachment form a monocyclicheterocycloalkyl group; provided that R² and R³ are not both H; or,alternatively, R² and R³ taken together with the nitrogen to which theyare attached form a saturated monocyclic heterocycloalkyl groupunsubstituted or substituted on a carbon ring member with one, two, orthree R^(d) moieties and substituted on a nitrogen ring member with anR^(e) moiety; where each R^(d) moiety is independently selected from thegroup consisting of: —C₁₋₆alkyl; —C₁₋₄alkyl-OH; halo; —OH; —OC₁₋₆alkyl;ipso-substituted —OC₂₋₃alkylO—; —CN; —NO₂; —N(R^(g))R^(h);—C(O)N(R^(g))R^(h); —N(R^(g))SO₂C₁₋₆alkyl; —C(O)C₁₋₆alkyl;—S(O)₀₋₂—C₁₋₆alkyl; —SO₂N(R^(g))R^(h); —SCF₃; —CF₃; —OCF₃; —CO₂H; and—CO₂C₁₋₆alkyl; where R^(g) and R^(h) are each independently —H or—C₁₋₆alkyl, or R^(g) and R^(h) taken together with their nitrogen ofattachment form a monocyclic heterocycloalkyl group; and where R^(e) isselected from the group consisting of: —H; a —C₁₋₆alkyl or—C(O)C₁₋₆alkyl group unsubstituted or substituted with halo, —CN, —OH,—OC₁₋₄alkyl, or —CF₃; —C(O)CF₃; —S(O)₀₋₂—C₁₋₆alkyl; —CO₂C₁₋₆alkyl; and aphenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, ormonocyclic carbon-linked heterocycloalkyl group, each unsubstituted orsubstituted with —C₁₋₄alkyl, halo, —CN, —OH, —OC₁₋₄alkyl, or —CF₃; q is0 or 1; each R⁴ is independently —H or methyl, or both R⁴ substituentstaken together form a carbonyl; Y is —O—, —OCH₂—, —S—, —SO—, or —SO₂—;R⁵ is —H or —C₁₋₆alkyl; R⁶ is —H; or —C₁₋₆alkyl, —C₃₋₆alkenyl,—C₃₋₆alkynyl, monocyclic cycloalkyl, or —C₁₋₆alkyl-(monocycliccycloalkyl), each unsubstituted or substituted with —C₁₋₄alkyl, —OH,—OC₁₋₄alkyl, halo, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, —CO₂H, or—CO₂C₁₋₄alkyl; R⁷ is —H; or —C₁₋₆alkyl, —C₃₋₆alkenyl, —C₃₋₆alkynyl,monocyclic cycloalkyl, or —C₁₋₆alkyl-(monocyclic cycloalkyl), eachunsubstituted or substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, —CO₂H, or —CO₂C₁₋₄alkyl; orR⁶ and R⁷ taken together with their nitrogen of attachment form asaturated monocyclic heterocycloalkyl group unsubstituted or substitutedwith —C₁₋₄alkyl, —OC₁₋₄alkyl, or halo; and Cyc is a phenyl or monocycliccarbon-linked heteroaryl group, unsubstituted or substituted with one,two, or three R^(k) moieties; where each R^(k) moiety is independentlyselected from the group consisting of: —C₁₋₆alkyl, —CHF₂, —CF₃,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —OH, —OC₁₋₆alkyl, —OCHF₂, —OCF₃,—OC₃₋₆alkenyl, —OC₃₋₆alkynyl, —CN, —NO₂, —N(R^(l))R^(m),—N(R^(l))C(O)R^(m), —N(R^(l))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —C(O)N(R^(l))R^(m), —SO₂N(R^(l))R^(m), —SCF₃, halo,—CO₂H, and —CO₂C₁₋₆alkyl; or two R^(k) moieties on adjacent carbon atomsof attachment together are —OC₁₋₄alkyleneO— to form a cyclic ring whichis unsubstituted or substituted with one or two fluoro substituents;where R^(l) and R^(m) are each independently —H or —C₁₋₆alkyl; providedthat when both R⁴ substituents taken together form a carbonyl, then R²and R³ taken together are not diazepanyl; or a pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, orpharmaceutically active metabolite thereof; and (b) a pharmaceuticallyacceptable excipient.
 36. A pharmaceutical composition according toclaim 35, further comprising: an active ingredient selected from thegroup consisting of H₁ receptor antagonists, H₂ receptor antagonists, H₃receptor antagonists, serotonin-norepinephrine reuptake inhibitors,selective serotonin reuptake inhibitors, noradrenergic reuptakeinhibitors, non-selective serotonin re-uptake inhibitors,acetylcholinesterase inhibitors, and modafinil.
 37. A method of treatinga subject suffering from or diagnosed with a disease, disorder, ormedical condition mediated by histamine H₃ receptor and/or serotonintransporter activity, comprising administering to the subject in need ofsuch treatment an effective amount of a compound of Formula (I):

wherein one of R^(1a) and R^(1b) is

 and the other is —H; R² and R³ are each independently selected from thegroup consisting of: —H; a —C₁₋₆alkyl group unsubstituted or substitutedwith —OH, —OC₁₋₄alkyl, —NH₂, —N(R^(a))R^(b), or —F; —CO₂C₁₋₄alkyl; and amonocyclic cycloalkyl group unsubstituted or substituted with—C₁₋₄alkyl, —OH, halo, or —CF₃; where R^(a) and R^(b) are eachindependently —H, —C₁₋₆alkyl, or monocyclic cycloalkyl, or R^(a) andR^(b) taken together with their nitrogen of attachment form a monocyclicheterocycloalkyl group; provided that R² and R³ are not both H; or,alternatively, R² and R³ taken together with the nitrogen to which theyare attached form a saturated monocyclic heterocycloalkyl groupunsubstituted or substituted on a carbon ring member with one, two, orthree R^(d) moieties and substituted on a nitrogen ring member with anR^(e) moiety; where each R^(d) moiety is independently selected from thegroup consisting of: —C₁₋₆alkyl; —C₁₋₄alkyl-OH; halo; —OH; —OC₁₋₆alkyl;ipso-substituted —OC₂₋₃alkylO—; —CN; —NO₂; —N(R^(g))R^(h); h—C(O)N(R^(g))R^(h); —N(R^(g))SO₂C₁₋₆alkyl; —C(O)C₁₋₆alkyl;—S(O)₀₋₂—C₁₋₆alkyl; —SO₂N(R^(g))R^(h); —SCF₃; —CF₃; —OCF₃; —CO₂H; and—CO₂C₁₋₆alkyl; where R^(g) and R^(h) are each independently —H or—C₁₋₆alkyl, or R^(g) and R^(h) taken together with their nitrogen ofattachment form a monocyclic heterocycloalkyl group; and where R^(e) isselected from the group consisting of: —H; a —C₁₋₆alkyl or—C(O)C₁₋₆alkyl group unsubstituted or substituted with halo, —CN, —OH,—OC₁₋₄alkyl, or —CF₃; —C(O)CF₃; —S(O)₀₋₂—C₁₋₆alkyl; —CO₂C₁₋₆alkyl; and aphenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, ormonocyclic carbon-linked heterocycloalkyl group, each unsubstituted orsubstituted with —C₁₋₄alkyl, halo, —CN, —OH, —OC₁₋₄alkyl, or —CF₃; q is0 or 1; each R⁴ is independently —H or methyl, or both R⁴ substituentstaken together form a carbonyl; Y is —O—, —OCH₂—, —S—, —SO—, or —SO₂—;R⁵ is —H or —C₁₋₆alkyl; R⁵ is —H; or —C₁₋₆alkyl, —C₃₋₆alkenyl,—C₃₋₆alkynyl, monocyclic cycloalkyl, or —C₁₋₆alkyl-(monocycliccycloalkyl), each unsubstituted or substituted with —C₁₋₄alkyl, —OH,—OC₁₋₄alkyl, halo, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, —CO₂H, or—CO₂C₁₋₄alkyl; R⁷ is —H; or —C₁₋₆alkyl, —C₃₋₆alkenyl, —C₃₋₆alkynyl,monocyclic cycloalkyl, or —C₁₋₆alkyl-(monocyclic cycloalkyl), eachunsubstituted or substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, —CO₂H, or —CO₂C₁₋₄alkyl; orR⁶ and R⁷ taken together with their nitrogen of attachment form asaturated monocyclic heterocycloalkyl group unsubstituted or substitutedwith —C₁₋₄alkyl, —OC₁₋₄alkyl, or halo; and Cyc is a phenyl or monocycliccarbon-linked heteroaryl group, unsubstituted or substituted with one,two, or three R^(k) moieties; where each R^(k) moiety is independentlyselected from the group consisting of: —C₁₋₆alkyl, —CHF₂, —CF₃,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —OH, —OC₁₋₆alkyl, —OCHF₂, —OCF₃,—OC₃₋₆alkenyl, —OC₃₋₆alkynyl, —CN, —NO₂, —N(R^(l))R^(m),—N(R^(l))C(O)R^(m), —N(R^(l))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —C(O)N(R^(l))R^(m), —SO₂N(R^(l))R^(m), —SCF₃, halo,—CO₂H, and —CO₂C₁₋₆alkyl; or two R^(k) moieties on adjacent carbon atomsof attachment together are —OC₁₋₄alkyleneO— to form a cyclic ring whichis unsubstituted or substituted with one or two fluoro substituents;where R^(l) and R^(m) are each independently —H or —C₁₋₆alkyl; providedthat when both R⁴ substituents taken together form a carbonyl, then R²and R³ taken together are not diazepanyl; or a pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, orpharmaceutically active metabolite thereof.
 38. The method according toclaim 37, wherein the disease, disorder, or medical condition isselected from the group consisting of: cognitive disorders, sleepdisorders, psychiatric disorders, and other disorders.
 39. The methodaccording to claim 37, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: dementia,Alzheimer's disease, cognitive dysfunction, mild cognitive impairment,pre-dementia, attention deficit hyperactivity disorders,attention-deficit disorders, and learning and memory disorders.
 40. Themethod according to claim 37, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: learning impairment,memory impairment, and memory loss.
 41. The method according to claim37, wherein the disease, disorder, or medical condition is selected fromthe group consisting of: insomnia, disturbed sleep, narcolepsy with orwithout associated cataplexy, cataplexy, disorders of sleep/wakehomeostasis, idiopathic somnolence, excessive daytime sleepiness,circadian rhythm disorders, fatigue, lethargy, and jet lag.
 42. Themethod according to claim 37, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: sleep apnea,perimenopausal hormonal shifts, Parkinson's disease, multiple sclerosis,depression, chemotherapy, and shift work schedules.
 43. The methodaccording to claim 37, wherein the disease, disorder, or medicalcondition is selected from the group consisting of: schizophrenia,bipolar disorders, manic disorders, depression, obsessive-compulsivedisorder, and post-traumatic stress disorder.
 44. The method accordingto claim 37, wherein the disease, disorder, or medical condition isselected from the group consisting of: motion sickness, vertigo,epilepsy, migraine, neurogenic inflammation, eating disorders, obesity,and substance abuse disorders.
 45. The method according to claim 37,wherein the disease, disorder, or medical condition is selected from thegroup consisting of: depression, disturbed sleep, fatigue, lethargy,cognitive impairment, memory impairment, memory loss, learningimpairment, attention-deficit disorders, and eating disorders.
 46. Apharmaceutical composition according to claim 35, further comprisingtopiramate.
 47. The method according to claim 37, wherein the disease,disorder, or medical condition is selected from the group consisting of:age-related cognitive decline, REM-behavioral disorder, benign posturalvertigo, tinitus, movement disorders, restless leg syndrome, eye-relateddisorders, macular degeneration, and retinitis pigmentosis.